For years, it has been held that cathepsin D (CD) is involved in rather non-specific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development, but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans. In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling. Moreover, procathepsin D (pCD), secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy. Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell-pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above-mentioned processes. In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

Laboratory of Cell Differentiation Department of Experimental Biology Faculty of Science Masaryk University ILBIT A3 Kamenice 3 Brno 625 00 Czech Republic

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Hasilik A, Neufeld EF. Biosynthesis of lysosomal enzymes in fibroblasts. Synthesis as precursors of higher molecular weight. J Biol Chem. 1980;255:4937–4945. PubMed

Kornfeld S. Lysosomal enzyme targeting. Biochem Soc Trans. 1990;18:367–374. PubMed

Hasilik A, Neufeld EF. Biosynthesis of lysosomal enzymes in fibroblasts. Phosphorylation of mannose residues. J Biol Chem. 1980;255:4946–4950. PubMed

Fortenberry SC, Schorey JS, Chirgwin JM. Role of glycosylation in the expression of human procathepsin D. J Cell Sci. 1995;108:2001–2006. PubMed

von Figura K, Hasilik A. Lysosomal enzymes and their receptors. Annu Rev Biochem. 1986;55:167–193. PubMed

Rijnboutt S, Kal AJ, Geuze HJ, Aerts H, Strous GJ. Mannose 6-phosphate-independent targeting of cathepsin D to lysosomes in HepG2 cells. J Biol Chem. 1991;266:23586–23592. PubMed

Zhu Y, Conner GE. Intermolecular association of lysosomal protein precursors during biosynthesis. J Biol Chem. 1994;269:3846–3851. PubMed

Capony F, Braulke T, Rougeot C, Roux S, Montcourrier P, Rochefort H. Specific mannose-6-phosphate receptor-independent sorting of pro-cathepsin D in breast cancer cells. Exp Cell Res. 1994;215:154–163. PubMed

Dittmer F, Ulbrich EJ, Hafner A, Schmahl W, Meister T, Pohlmann R, et al. Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific. J Cell Sci. 1999;112:1591–1597. PubMed

Gopalakrishnan MM, Grosch HW, Locatelli-Hoops S, Werth N, Smolenová E, Nettersheim M, et al. Purified recombinant human prosaposin forms oligomers that bind procathepsin D and affect its autoactivation. Biochem J. 2004;383:507–515. PubMed PMC

Erickson AH, Conner GE, Blobel G. Biosynthesis of a lysosomal enzyme. Partial structure of two transient and functionally distinct NH2-terminal sequences in cathepsin D. J Biol Chem. 1981;256:11224–11231. PubMed

Conner GE, Richo G. Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D. Biochemistry. 1992;31:1142–1147. PubMed

Gieselmann V, Hasilik A, von Figura K. Processing of human cathepsin D in lysosomes in vitro. J Biol Chem. 1985;260:3215–3220. PubMed

Hentze M, Hasilik A, von Figura K. Enhanced degradation of cathepsin D synthesized in the presence of the threonine analog beta-hydroxynorvaline. Arch Biochem Biophys. 1984;230:375–382. PubMed

Samarel AM, Ferguson AG, Decker RS, Lesch M. Effects of cysteine protease inhibitors on rabbit cathepsin D maturation. Am J Physiol. 1989;257:1069–1079. PubMed

Richo G, Conner GE. Proteolytic activation of human procathepsin D. Adv Exp Med Biol. 1991;306:289–296. PubMed

Wittlin S, Rösel J, Hofmann F, Stover DR. Mechanisms and kinetics of procathepsin D activation. Eur J Biochem. 1999;265:384–393. PubMed

Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 1999;18:5252–5263. PubMed PMC

Eder J, Hommel U, Cumin F, Martoglio B, Gerhartz B. Aspartic proteases in drug discovery. Curr Pharm Des. 2007;13:271–285. PubMed

Vetvicka V, Vagner J, Baudys M, Tang J, Foundling SI, Fusek M. Human breast milk contains procathepsin D-detection by specific antibodies. Biochem Mol Biol Int. 1993;30:921–928. PubMed

Larsen LB, Petersen TE. Identification of five molecular forms of cathepsin D in bovine milk. Adv Exp Med Biol. 1995;362:279–283. PubMed

Benes P, Koelsch G, Dvorak B, Fusek M, Vetvicka V. Detection of procathepsin D in rat milk. Comp Biochem Physiol B Biochem Mol Biol. 2002;133:113–118. PubMed

Zühlsdorf M, Imort M, Hasilik A, von Figura K. Molecular forms of beta-hexosaminidase and cathepsin D in serum and urine of healthy subjects and patients with elevated activity of lysosomal enzymes. Biochem J. 1983;213:733–740. PubMed PMC

Baechle D, Flad T, Cansier A, Steffen H, Schittek B, Tolson J, et al. Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L. J Biol Chem. 2006;281:5406–5415. PubMed

Leto G, Tumminello FM, Crescimanno M, Flandina C, Gebbia N. Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications. Clin Exp Metastasis. 2004;21:91–106. PubMed

Laurent-Matha V, Farnoud MR, Lucas A, Rougeot C, Garcia M, Rochefort H. Endocytosis of pro-cathepsin D into breast cancer cells is mostly independent of mannose-6-phosphate receptors. J Cell Sci. 1998;111:2539–2549. PubMed

Laurent-Matha V, Maruani-Herrmann S, Prébois C, Beaujouin M, Glondu M, Noël A, et al. Catalytically inactive human cathepsin D triggers fibroblast invasive growth. J Cell Biol. 2005;168:489–499. PubMed PMC

Poole AR, Hembry RM, Dingle JT. Cathepsin D in cartilage: the immunohistochemical demonstration of extracellular enzyme in normal and pathological conditions. J Cell Sci. 1974;14:139–161. PubMed

Poole AR, Hembry RM, Dingle JT, Pinder I, Ring EF, Cosh J. Secretion and localization of cathepsin D in synovial tissues removed from rheumatoid and traumatized joints. An immunohistochemical study. Arthritis Rheum. 1976;19:1295–1307. PubMed

Bjelle A, Osterlin S. Cathepsin D activity in bovine articular cartilage, synovial membrane and fluid: degradation of cartilage proteoglycans from same joint. J Rheumatol. 1976;3:400–408. PubMed

Vittorio N, Crissman JD, Hopson CN, Herman JH. Histologic assessment of cathepsin D in osteoarthritic cartilage. Clin Exp Rheumatol. 1986;4:221–230. PubMed

Hakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, et al. Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2003;23:1430–1436. PubMed

Vashishta A, Saraswat Ohri S, Vetvickova J, Fusek M, Ulrichova J, Vetvicka V. Procathepsin D secreted by HaCaT keratinocyte cells - A novel regulator of keratinocyte growth. Eur J Cell Biol. 2007;86:303–313. PubMed PMC

Dunn BM, Scarborough PE, Lowther WT, Rao-Naik C. Comparison of the active site specificity of the aspartic proteinases based on a systematic series of peptide substrates. Adv Exp Med Biol. 1995;362:1–9. PubMed

Dunn BM, Hung S. The two sides of enzyme-substrate specificity: lessons from the aspartic proteinases. Biochim Biophys Acta. 2000;1477:231–240. PubMed

Bankowska A, Gacko M, Chyczewska E, Worowska A. Biological and diagnostic role of cathepsin D. Rocz Akad Med Bialymst. 1997;42 Suppl 1:79–85. PubMed

Takei Y, Higashira H, Yamamoto T, Hayashi K. Mitogenic activity toward human breast cancer cell line MCF-7 of two bFGFs purified from sera of breast cancer patients: co-operative role of cathepsin D. Breast Cancer Res Treat. 1997;43:53–63. PubMed

Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi J, et al. Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. J Biol Chem. 2000;275:38912–38920. PubMed

Piwnica D, Touraine P, Struman I, Tabruyn S, Bolbach G, Clapp C, et al. Cathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: study of their antiangiogenic properties and physiological relevance. Mol Endocrinol. 2004;18:2522–2542. PubMed

Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. J Cell Sci. 2004;117:5155–5164. PubMed

Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaissé J. Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett. 2000;486:247–251. PubMed

Baumgrass R, Williamson MK, Price PA. Identification of peptide fragments generated by digestion of bovine and human osteocalcin with the lysosomal proteinases cathepsin B, D, L, H, and S. J Bone Miner Res. 1997;12:447–455. PubMed

Dunn AD, Crutchfield HE, Dunn JT. Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L. J Biol Chem. 1991;266:20198–20204. PubMed

Woessner JF, Jr, Shamberger RJ., Jr Purification and properties of cathepsin D from bovine utrus. J Biol Chem. 1971;246:1951–1960. PubMed

Authier F, Mort JS, Bell AW, Posner BI, Bergeron JJ. Proteolysis of glucagon within hepatic endosomes by membrane-associated cathepsins B and D. J Biol Chem. 1995;270:15798–15807. PubMed

Kudo S, Miyamoto G, Kawano K. Proteases involved in the metabolic degradation of human interleukin-1beta by rat kidney lysosomes. J Interferon Cytokine Res. 1999;19:361–367. PubMed

Nunn SE, Peehl DM, Cohen P. Acid-activated insulin-like growth factor binding protein protease activity of cathepsin D in normal and malignant prostatic epithelial cells and seminal plasma. J Cell Physiol. 1997;171:196–204. PubMed

Mordente JA, Choudhury MS, Tazaki H, Mallouh C, Konno S. Hydrolysis of androgen receptor by cathepsin D: its biological significance in human prostate cancer. Br J Urol. 1998;82:431–435. PubMed

Diment S, Martin KJ, Stahl PD. Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins. J Biol Chem. 1989;264:13403–13406. PubMed

Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L. Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Am J Pathol. 2003;162:1183–1190. PubMed PMC

Nishimura Y, Kawabata T, Kato K. Identification of latent procathepsins B and L in microsomal lumen: characterization of enzymatic activation and proteolytic processing in vitro. Arch Biochem Biophys. 1988;261:64–71. PubMed

van der Stappen JW, Williams AC, Maciewicz RA, Paraskeva C. Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D. Int J Cancer. 1996;67:547–554. PubMed

Nishimura Y, Kawabata T, Furuno K, Kato K. Evidence that aspartic proteinase is involved in the proteolytic processing event of procathepsin L in lysosomes. Arch Biochem Biophys. 1989;271:400–406. PubMed

Egberts F, Heinrich M, Jensen JM, Winoto-Morbach S, Pfeiffer S, Wickel M, et al. Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. J Cell Sci. 2004;117:2295–2307. PubMed

Sadik G, Kaji H, Takeda K, Yamagata F, Kameoka Y, Hashimoto K, et al. In vitro processing of amyloid precursor protein by cathepsin D. Int J Biochem Cell Biol. 1999;31:1327–1337. PubMed

Ladror US, Snyder SW, Wang GT, Holzman TF, Krafft GA. Cleavage at the amino and carboxyl termini of Alzheimer's amyloid-beta by cathepsin D. J Biol Chem. 1994;269:18422–18428. PubMed

Kenessey A, Nacharaju P, Ko LW, Yen SH. Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration. J Neurochem. 1997;69:2026–2038. PubMed

Banay-Schwartz M, Bracco F, DeGuzman T, Lajtha A. Developmental changes in the breakdown of brain tubulin by cerebral cathepsin D. Neurochem Res. 1983;8:51–61. PubMed

Benuck M, Marks N, Hashim GA. Metabolic instability of myelin proteins. Breakdown of basic protein induced by brain cathepsin D. Eur J Biochem. 1975;52:615–621. PubMed

Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, et al. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis. 2006;22:346–356. PubMed

Zhou W, Scott SA, Shelton SB, Crutcher KA. Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer's disease. Neuroscience. 2006;143:689–701. PubMed

Takahashi M, Ko LW, Kulathingal J, Jiang P, Sevlever D, Yen SH. Oxidative stress-induced phosphorylation, degradation and aggregation of alpha-synuclein are linked to upregulated CK2 and cathepsin D. Eur J Neurosci. 2007;26:863–874. PubMed

Banay-Schwartz M, Dahl D, Hui KS, Lajtha A. The breakdown of the individual neurofilament proteins by cathepsin D. Neurochem Res. 1987;12:361–367. PubMed

Bird JW, Schwartz WN, Spanier AM. Degradation of myofibrillar proteins by cathepsins B and D. Acta Biol Med Ger. 1977;36:1587–1604. PubMed

Jones TL, Ogunro EA, Samarel AM, Ferguson AG, Lesch M. Susceptibilities of cardiac myofibrillar proteins to cathepsin D-catalyzed degradation. Am J Physiol. 1983;245:294–299. PubMed

Okitani A, Matsumoto T, Kitamura Y, Kato H. Purification of cathepsin D from rabbit skeletal muscle and its action towards myofibrils. Biochim Biophys Acta. 1981;662:202–209. PubMed

Simon DI, Ezratty AM, Loscalzo J. The fibrin(ogen)olytic properties of cathepsin D. Biochemistry. 1994;33:6555–6563. PubMed

Loscalzo J. The macrophage and fibrinolysis. Semin Thromb Hemost. 1996;22:503–506. PubMed

Heinrich M, Neumeyer J, Jakob M, Hallas C, Tchikov V, Winoto-Morbach S, et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 2004;11:550–563. PubMed

Haendeler J, Popp R, Goy C, Tischler V, Zeiher AM, Dimmeler S. Cathepsin D and H2O2 stimulate degradation of thioredoxin-1: implication for endothelial cell apoptosis. J Biol Chem. 2005;280:42945–42951. PubMed

Hiraiwa M, Martin BM, Kishimoto Y, Conner GE, Tsuji S, O'Brien JS. Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): its mechanism and inhibition by ganglioside. Arch Biochem Biophys. 1997;341:17–24. PubMed

Pimenta DC, Chen VC, Chao J, Juliano MA, Juliano L. Alpha1-antichymotrypsin and kallistatin hydrolysis by human cathepsin D. J Protein Chem. 2000;19:411–418. PubMed

Lenarcic B, Krasovec M, Ritonja A, Olafsson I, Turk V. Inactivation of human cystatin C and kininogen by human cathepsin D. FEBS Lett. 1991;280:211–215. PubMed

van der Westhuyzen DR, Gevers W, Coetzee GA. Cathepsin-D-dependent initiation of the hydrolysis by lysosomal enzymes of apoprotein B from low-density lipoproteins. Eur J Biochem. 1980;112:153–160. PubMed

Roughley PJ. The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan heterogeneity and the pathway of proteolytic degradation. Biochem J. 1977;167:639–646. PubMed PMC

Handley CJ, Mok MT, Ilic MZ, Adcocks C, Buttle DJ, Robinson HC. Cathepsin D cleaves aggrecan at unique sites within the interglobular domain and chondroitin sulfate attachment regions that are also cleaved when cartilage is maintained at acid pH. Matrix Biol. 2001;20:543–553. PubMed

Scott PG, Pearson CH. Cathepsin D: cleavage of soluble collagen and crosslinked peptides. FEBS Lett. 1978;88:41–45. PubMed

Scott PG, Pearson H. Cathepsin D: specificity of peptide-bond cleavage in type-I collagen and effects on type-III collagen and procollagen. Eur J Biochem. 1981;114:59–62. PubMed

Tressel T, Shively JE, Pande H. Human placental fibronectin: demonstration of structural differences between the A and B chains in the extra domain-A region. Arch Biochem Biophys. 1988;266:639–643. PubMed

Hultquist DE, Rodriguez C, Schafer DA. Cathepsin D in erythroid cells. Prog Clin Biol Res. 1989;319:93–101. PubMed

Kim K, Homma Y, Ikeuchi Y, Suzuki A. Cleavage of connectin by calpain and cathepsin D. Biosci Biotechnol Biochem. 1995;59:896–899. PubMed

Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J. 1995;14:3599–3608. PubMed PMC

Guicciardi ME, Leist M, Gores GJ. Lysosomes in cell death. Oncogene. 2004;23:2881–2890. PubMed

Koike M, Shibata M, Ohsawa Y, Nakanishi H, Koga T, Kametaka S, et al. Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice. Mol Cell Neurosci. 2003;22:146–161. PubMed

Myllykangas L, Tyynelä J, Page-McCaw A, Rubin GM, Haltia MJ, Feany MB. Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses. Neurobiol Dis. 2005;19:194–199. PubMed

Tyynelä J, Sohar I, Sleat DE, Gin RM, Donnelly RJ, Baumann M, et al. A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J. 2000;19:2786–2792. PubMed PMC

Tyynelä J, Sohar I, Sleat DE, Gin RM, Donnelly RJ, Baumann M, et al. Congenital ovine neuronal ceroid lipofuscinosis-a cathepsin D deficiency with increased levels of the inactive enzyme. Eur J Paediatr Neurol. 2001;5 Suppl A:43–45. PubMed

Awano T, Katz ML, O'Brien DP, Taylor JF, Evans J, Khan S, et al. A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006;87:341–348. PubMed

Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W, et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78:988–998. PubMed PMC

Siintola E, Partanen S, Strömme P, Haapanen A, Haltia M, Maehlen J, et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006;129:1438–1445. PubMed

Partanen S, Storch S, Löffler HG, Hasilik A, Tyynelä J, Braulke T. A replacement of the active-site aspartic acid residue 293 in mouse cathepsin D affects its intracellular stability, processing and transport in HEK-293 cells. Biochem J. 2003;369:55–62. PubMed PMC

Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, et al. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci. 2000;20:6898–6906. PubMed PMC

Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, et al. Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease) Am J Pathol. 2005;167:1713–1728. PubMed PMC

Walls KC, Klocke BJ, Saftig P, Shibata M, Uchiyama Y, Roth KA, et al. Altered regulation of phosphatidylinositol 3-kinase signaling in cathepsin D-deficient brain. Autophagy. 2007;3:222–229. PubMed

Shacka JJ, Klocke BJ, Young C, Shibata M, Olney JW, Uchiyama Y, et al. Cathepsin D deficiency induces persistent neurodegeneration in the absence of Bax-dependent apoptosis. J Neurosci. 2007;27:2081–2090. PubMed PMC

Zhang D, Brankov M, Makhija MT, Robertson T, Helmerhorst E, Papadimitriou JM, et al. Correlation between inactive cathepsin D expression and retinal changes in mcd2/mcd2 transgenic mice. Invest Ophthalmol Vis Sci. 2005;46:3031–3038. PubMed

Chen SH, Arany I, Apisarnthanarax N, Rajaraman S, Tyring SK, Horikoshi T, et al. Response of keratinocytes from normal and psoriatic epidermis to interferon-gamma differs in the expression of zinc-alpha(2)-glycoprotein and cathepsin D. FASEB J. 2000;14:565–571. PubMed

Kawada A, Hara K, Kominami E, Hiruma M, Noguchi H, Ishibashi A. Processing of cathepsins L, B and D in psoriatic epidermis. Arch Dermatol Res. 1997;289:87–93. PubMed

Kim SY, Chung SI, Yoneda K, Steinert PM. Expression of transglutaminase 1 in human epidermis. J Invest Dermatol. 1995;104:211–217. PubMed

Negi M, Matsui T, Ogawa H. Mechanism of regulation of human epidermal transglutaminase. J Invest Dermatol. 1981;77:389–392. PubMed

Negi M, Park JK, Ogawa H. Alteration of human epidermal transglutaminase during its activation. J Dermatol Sci. 1990;1:167–171. PubMed

Steinert PM, Chung SI, Kim SY. Inactive zymogen and highly active proteolytically processed membrane-bound forms of the transglutaminase 1 enzyme in human epidermal keratinocytes. Biochem Biophys Res Commun. 1996;221:101–106. PubMed

Kim SY, Bae CD. Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. Exp Mol Med. 1998;30:257–262. PubMed

Bröker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res. 2005;11:3155–3162. PubMed

Li W, Yuan X, Nordgren G, Dalen H, Dubowchik GM, Firestone RA, et al. Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett. 2000;470:35–39. PubMed

Boya P, Gonzalez-Polo RA, Poncet D, Andreau K, Vieira HL, Roumier T, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003;22:3927–3936. PubMed

Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Exp Med. 2003;197:1323–1334. PubMed PMC

Bidère N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, et al. Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J Biol Chem. 2003;278:31401–31411. PubMed

Roberg K, Ollinger K. Oxidative stress causes relocation of the lysosomal enzyme cathepsin D with ensuing apoptosis in neonatal rat cardiomyocytes. Am J Pathol. 1998;152:1151–1156. PubMed PMC

Persson HL, Yu Z, Tirosh O, Eaton JW, Brunk UT. Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Radic Biol Med. 2003;34:1295–1305. PubMed

Castino R, Bellio N, Nicotra G, Follo C, Trincheri NF, Isidoro C. Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells. Free Radic Biol Med. 2007;42:1305–1316. PubMed

Kagedal K, Johansson AC, Johansson U, Heimlich G, Roberg K, Wang NS, et al. Lysosomal membrane permeabilization during apoptosis-involvement of Bax? Int J Exp Pathol. 2005;86:309–321. PubMed PMC

Kagedal K, Zhao M, Svensson I, Brunk UT. Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem J. 2001;359:335–343. PubMed PMC

Zhao M, Antunes F, Eaton JW, Brunk UT. Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis. Eur J Biochem. 2003;270:3778–3786. PubMed

Kolesnick R, Hannun YA. Ceramide and apoptosis. Trends Biochem Sci. 1999;24:224–225. PubMed

Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000;10:73–80. PubMed

De Stefanis D, Reffo P, Bonelli G, Baccino FM, Sala G, Ghidoni R, et al. Increase in ceramide level alters the lysosomal targeting of cathepsin D prior to onset of apoptosis in HT-29 colon cancer cells. Biol Chem. 2002;383:989–999. PubMed

Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J. 1996;15:3861–3870. PubMed PMC

Roberg K, Kagedal K, Ollinger K. Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts. Am J Pathol. 2002;161:89–96. PubMed PMC

Schestkowa O, Geisel D, Jacob R, Hasilik A. The catalytically inactive precursor of cathepsin D induces apoptosis in human fibroblasts and HeLa cells. J Cell Biochem. 2007;101:1558–1566. PubMed

Emert-Sedlak L, Shangary S, Rabinovitz A, Miranda MB, Delach SM, Johnson DE. Involvement of cathepsin D in chemotherapy-induced cytochrome c release, caspase activation, and cell death. Mol Cancer Ther. 2005;4:733–742. PubMed

Wu GS, Saftig P, Peters C, El-Deiry WS. Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. Oncogene. 1998;16:2177–2183. PubMed

Trincheri NF, Nicotra G, Follo C, Castino R, Isidoro C. Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D. Carcinogenesis. 2007;28:922–931. PubMed

Beaujouin M, Baghdiguian S, Glondu-Lassis M, Berchem G, Liaudet-Coopman E. Overexpression of both catalytically-active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity. Oncogene. 2006;25:1967–1973. PubMed PMC

Shibata M, Kanamori S, Isahara K, Ohsawa Y, Konishi A, Kametaka S, et al. Participation of cathepsins B and D in apoptosis of PC12 cells following serum deprivation. Biochem Biophys Res Commun. 1998;251:199–203. PubMed

Roberg K, Johansson U, Ollinger K. Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress. Free Radic Biol Med. 1999;27:1228–1237. PubMed

Kagedal K, Johansson U, Ollinger K. The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. FASEB J. 2001;15:1592–1594. PubMed

Tardy C, Tyynelä J, Hasilik A, Levade T, Andrieu-Abadie N. Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D. Cell Death Differ. 2003;10:1090–1100. PubMed

Reiners JJ, Jr, Caruso JA, Mathieu P, Chelladurai B, Yin XM, Kessel D. Release of cytochrome c and activation of pro-caspase-9 following lysosomal photodamage involves Bid cleavage. Cell Death Differ. 2002;9:934–944. PubMed PMC

Berchem G, Glondu M, Gleizes M, Brouillet JP, Vignon F, Garcia M, et al. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene. 2002;21:5951–5955. PubMed

Zaidi N, Burster T, Sommandas V, Herrmann T, Boehm BO, Driessen C, et al. A novel cell penetrating aspartic protease inhibitor blocks processing and presentation of tetanus toxoid more efficiently than pepstatin A. Biochem Biophys Res Commun. 2007;364:243–249. PubMed

Bessodes M, Antonakis K, Herscovici J, Garcia M, Rochefort H, Capony F, et al. Inhibition of cathepsin D by tripeptides containing statine analogs. Biochem Pharmacol. 1999:58329–58333. PubMed

Yoshida H, Okamoto K, Iwamoto T, Sakai E, Kanaoka K, Hu JP, et al. Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation. J Biochem. 2006;139:583–590. PubMed

Schotte P, Declercq W, Van Huffel S, Vandenabeele P, Beyaert R. Non-specific effects of methyl ketone peptide inhibitors of caspases. FEBS Lett. 1999;442:117–121. PubMed

Dash C, Kulkarni A, Dunn B, Rao M. Aspartic peptidase inhibitors: implications in drug development. Crit Rev Biochem Mol Biol. 2003;38:89–119. PubMed

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–766. PubMed

Cataldo AM, Paskevich PA, Kominami E, Nixon RA. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1991;88:10998–11002. PubMed PMC

Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, et al. Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron. 1995;14:671–680. PubMed

Cataldo AM, Nixon RA. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci U S A. 1990;87:3861–3865. PubMed PMC

Schwagerl AL, Mohan PS, Cataldo AM, Vonsattel JP, Kowall NW, Nixon RA. Elevated levels of the endosomal-lysosomal proteinase cathepsin D in cerebrospinal fluid in Alzheimer disease. J Neurochem. 1995;64:443–446. PubMed

Ginsberg SD, Hemby SE, Lee VM, Eberwine JH, Trojanowski JQ. Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons. Ann Neurol. 2000;48:77–87. PubMed

Spires TL, Hyman BT. Transgenic models of Alzheimer's disease: learning from animals. NeuroRx. 2005;2:423–437. PubMed PMC

Saftig P, Peters C, von Figura K, Craessaerts K, Van Leuven F, De Strooper B. Amyloidogenic processing of human amyloid precursor protein in hippocampal neurons devoid of cathepsin D. J Biol Chem. 1996;271:27241–27244. PubMed

Touitou I, Capony F, Brouillet JP, Rochefort H. Missense polymorphism (C/T224) in the human cathepsin D pro-fragment determined by polymerase chain reaction-single strand conformational polymorphism analysis and possible consequences in cancer cells. Eur J Cancer. 1994;30A:390–394. PubMed

Masa M, Maresova L, Vondrasek JR, Horn M, Jezek J, Mares M. Cathepsin d propeptide: mechanism and regulation of its interaction with the catalytic core. Biochemistry. 2006;45:15474–15482. PubMed

Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, et al. Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease. J Neurol Sci. 2006;247:187–191. PubMed

Heun R, Ptok U, Kölsch H, Maier W, Jessen F. Contribution of apolipoprotein E and cathepsin D genotypes to the familial aggregation of Alzheimer's disease. Dement Geriatr Cogn Disord. 2004;18:151–158. PubMed

Papassotiropoulos A, Bagli M, Kurz A, Kornhuber J, Förstl H, Maier W, et al. A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease. Ann Neurol. 2000;47:399–403. PubMed

Papassotiropoulos A, Lewis HD, Bagli M, Jessen F, Ptok U, Schulte A, et al. Cerebrospinal fluid levels of beta-amyloid(42) in patients with Alzheimer's disease are related to the exon 2 polymorphism of the cathepsin D gene. Neuroreport. 2002;13:1291–1294. PubMed

Riemenschneider M, Blennow K, Wagenpfeil S, Andreasen N, Prince JA, Laws SM, et al. The cathepsin D rs17571 polymorphism: effects on CSF tau concentrations in Alzheimer disease. Hum Mutat. 2006;27:532–537. PubMed

Davidson Y, Gibbons L, Pritchard A, Hardicre J, Wren J, Tian J, et al. Genetic associations between cathepsin D exon 2 C→T polymorphism and Alzheimer's disease, and pathological correlations with genotype. J Neurol Neurosurg Psychiatry. 2006;77:515–517. PubMed PMC

Ntais C, Polycarpou A, Ioannidis JP. Meta-analysis of the association of the cathepsin D Ala224Val gene polymorphism with the risk of Alzheimer's disease: a HuGE gene-disease association review. Am J Epidemiol. 2004;159:527–536. PubMed

Bertram L, McQueen M, Mullin K, Blacker D, Tanzi R. The AlzGene Database. Alzheimer Research Forum. [Accessed September 20th, 2007]. Available at http://www.alzforum.org/res/com/gen/alzgene/meta.asp?geneID=42. PubMed

Lusis AJ. Atherosclerosis. Nature. 2000;407:233–241. PubMed PMC

Duran MC, Martin-Ventura JL, Mohammed S, Barderas MG, Blanco-Colio LM, Mas S, et al. Atorvastatin modulates the profile of proteins released by human atherosclerotic plaques. Eur J Pharmacol. 2007;562:119–129. PubMed

Leake DS. Does an acidic pH explain why low density lipoprotein is oxidised in atherosclerotic lesions? Atherosclerosis. 1997;129:149–157. PubMed

Tapper H, Sundler R. Cytosolic pH regulation in mouse macrophages. Proton extrusion by plasma-membrane-localized H(+)-ATPase. Biochem J. 1992;281:245–250. PubMed PMC

Chen GC, Lau K, Hamilton RL, Kane JP. Differences in local conformation in human apolipoprotein B-100 of plasma low density and very low density lipoproteins as identified by cathepsin D. J Biol Chem. 1991;266:12581–12587. PubMed

Chen GC, Liu W, Duchateau P, Allaart J, Hamilton RL, Mendel CM, et al. Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). Association of altered proteolytic accessibility with decreased receptor binding of LDL subspecies from hypertriglyceridemic subjects. J Biol Chem. 1994;269:29121–29128. PubMed

Björkerud S, Björkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol. 1996;149:367–380. PubMed PMC

Yuan XM, Li W, Olsson AG, Brunk UT. The toxicity to macrophages of oxidized low-density lipoprotein is mediated through lysosomal damage. Atherosclerosis. 1997;133:153–161. PubMed

Hardwick SJ, Hegyi L, Clare K, Law NS, Carpenter KL, Mitchinson MJ, et al. Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein. J Pathol. 1996;179:294–302. PubMed

Mitchinson MJ, Ball RY, Carpenter KH, Enright JH, Brabbs CE. Ceroid, macrophages and atherosclerosis. Biochem Soc Trans. 1990;18:1066–1069. PubMed

Li W, Yuan XM, Brunk UT. OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron. Free Radic Res. 1998;29:389–398. PubMed

Li W, Yuan XM. Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis. Ann N Y Acad Sci. 2004;1030:427–433. PubMed

Haidar B, Kiss RS, Sarov-Blat L, Brunet R, Harder C, McPherson R, et al. Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux. J Biol Chem. 2006;281:39971–39981. PubMed

Reid WA, Valler MJ, Kay J. Immunolocalization of cathepsin D in normal and neoplastic human tissues. J Clin Pathol. 1986;39:1323–1330. PubMed PMC

Thorpe SM, Rochefort H, Garcia M, Freiss G, Christensen IJ, Khalaf S, et al. Association between high concentrations of Mr 52,000 cathepsin D and poor prognosis in primary human breast cancer. Cancer Res. 1989;49:6008–6014. PubMed

Spyratos F, Maudelonde T, Brouillet JP, Brunet M, Defrenne A, Andrieu C, et al. Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet. 1989;2:1115–1118. PubMed

Ioachin E. Immunohistochemical tumour markers in endometrial carcinoma. Eur J Gynaecol Oncol. 2005;26:363–371. PubMed

Cunat S, Hoffmann P, Pujol P. Estrogens and epithelial ovarian cancer. Gynecol Oncol. 2004;94:25–32. PubMed

Rochefort H, Liaudet-Coopman E. Cathepsin D in cancer metastasis: a protease and a ligand. APMIS. 1999;107:86–95. PubMed

Mirza AN, Mirza NQ, Vlastos G, Singletary SE. Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg. 2002;235:10–26. PubMed PMC

Ferrandina G, Scambia G, Bardelli F, Benedetti Panici P, Mancuso S, et al. Relationship between cathepsin-D content and disease-free survival in node-negative breast cancer patients: a meta-analysis. Br J Cancer. 1997;76:661–666. PubMed PMC

Foekens JA, Look MP, Bolt-de Vries J, Meijer-van Gelder ME, van Putten WL, Klijn JG. Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients. Br J Cancer. 1999;79:300–307. PubMed PMC

Billgren AM, Rutqvist LE, Johansson H, Hägerström T, Skoog L. The role of cathepsin D and PAI-1 in primary invasive breast cancer as prognosticators and predictors of treatment benefit with adjuvant tamoxifen. Eur J Cancer. 2000;36:1374–1380. PubMed

Rodríguez J, Vázquez J, Corte MD, Lamelas M, Bongera M, Corte MG, et al. Clinical significance of cathepsin D concentration in tumor cytosol of primary breast cancer. Int J Biol Markers. 2005;20:103–111. PubMed

Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–5312. PubMed

Vignon F, Capony F, Chambon M, Freiss G, Garcia M, Rochefort H. Autocrine growth stimulation of the MCF 7 breast cancer cells by the estrogen-regulated 52 K protein. Endocrinology. 1986;118:1537–1545. PubMed

Fusek M, Vetvicka V. Mitogenic function of human procathepsin D: the role of the propeptide. Biochem J. 1994;303:775–780. PubMed PMC

Vetvicka V, Vetvickova J, Fusek M. Effect of human procathepsin D on proliferation of human cell lines. Cancer Lett. 1994;79:131–135. PubMed

Vetvicka V, Vetvickova J, Fusek M. Effect of procathepsin D and its activation peptide on prostate cancer cells. Cancer Lett. 1998;129:55–59. PubMed

Vetvicka V, Vetvickova J, Fusek M. Role of procathepsin D activation peptide in prostate cancer growth. Prostate. 2000;44:1–7. PubMed

Bazzett LB, Watkins CS, Gercel-Taylor C, Taylor DD. Modulation of proliferation and chemosensitivity by procathepsin D and its peptides in ovarian cancer. Gynecol Oncol. 1999;74:181–187. PubMed

Vetvicka V, Vetvickova J, Benes P. Role of enzymatically inactive procathepsin D in lung cancer. Anticancer Res. 2004;24:2739–2743. PubMed

Vashishta A, Ohri SS, Proctor M, Fusek M, Vetvicka V. Role of activation peptide of procathepsin D in proliferation and invasion of lung cancer cells. Anticancer Res. 2006;26:4163–4170. PubMed

Glondu M, Liaudet-Coopman E, Derocq D, Platet N, Rochefort H, Garcia M. Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells. Oncogene. 2002;21:5127–5134. PubMed

Ohri SS, Vashishta A, Proctor M, Fusek M, Vetvicka V. Depletion of Procathepsin D Gene Expression by RNA Interference: A Potential Therapeutic Target for Breast Cancer. Cancer Biol Ther. 2007 in press. PubMed

Vashishta A, Ohri SS, Proctor M, Fusek M, Vetvicka V. Ribozyme-targeting procathepsin D and its effect on invasion and growth of breast cancer cells: an implication in breast cancer therapy. Int J Oncol. 2007;30:1223–1230. PubMed

Vetvicka V, Vetvickova J, Hilgert I, Voburka Z, Fusek M. Analysis of the interaction of procathepsin D activation peptide with breast cancer cells. Int J Cancer. 1997;73:403–409. PubMed

Vetvicka V, Vetvickova J, Fusek M. Anti-human procathepsin D activation peptide antibodies inhibit breast cancer development. Breast Cancer Res Treat. 1999;57:261–269. PubMed

Gerweck LE, Seetharaman K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 1996;56:1194–1198. PubMed

Montcourrier P, Silver I, Farnoud R, Bird I, Rochefort H. Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism. Clin Exp Metastasis. 1997;15:382–392. PubMed

Glondu M, Coopman P, Laurent-Matha V, Garcia M, Rochefort H, Liaudet-Coopman E. A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells. Oncogene. 2001;20:6920–6929. PubMed

Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H. Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res. 1989;49:3904–3909. PubMed

Maguchi S, Taniguchi N, Makita A. Elevated activity and increased mannose-6-phosphate in the carbohydrate moiety of cathepsin D from human hepatoma. Cancer Res. 1988;48:362–367. PubMed

Mathieu M, Rochefort H, Barenton B, Prebois C, Vignon F. Interactions of cathepsin-D and insulin-like growth factor-II (IGF-II) on the IGF-II/mannose-6-phosphate receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II. Mol Endocrinol. 1990;4:1327–1335. PubMed

Vignon F, Rochefort H. Interactions of pro-cathepsin D and IGF-II on the mannose-6-phosphate/IGF-II receptor. Breast Cancer Res Treat. 1992;22:47–57. PubMed

Vetvicka V, Benes P, Fusek M. Procathepsin D in breast cancer: what do we know? Effects of ribozymes and other inhibitors. Cancer Gene Ther. 2002;9:854–863. PubMed

Ohri SS, Vashishta A, Proctor M, Fusek M, Vetvicka V. The propeptide of cathepsin D increases proliferation, invasion and metastasis of breast cancer cells. Int J Oncol. 2008;32:491–498. PubMed

Baldwin ET, Bhat TN, Gulnik S, Hosur MV, Sowder RC, Cachau RE, et al. Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design. Proc Natl Acad Sci U S A. 1993;90:6796–6800. PubMed PMC

Metcalf P, Fusek M. Two crystal structures for cathepsin D: the lysosomal targeting signal and active site. EMBO J. 1993;12:1293–1302. PubMed PMC

Koelsch G, Metcalf P, Vetvicka V, Fusek M. Human procathepsin D: three-dimensional model and isolation. Adv Exp Med Biol. 1995;362:273–278. PubMed

Garcia M, Derocq D, Pujol P, Rochefort H. Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency. Oncogene. 1990;5:1809–1814. PubMed

Tedone T, Correale M, Barbarossa G, Casavola V, Paradiso A, Reshkin SJ. Release of the aspartyl protease cathepsin D is associated with and facilitates human breast cancer cell invasion. FASEB J. 1997;11:785–792. PubMed

Sivaparvathi M, Sawaya R, Chintala SK, Go Y, Gokaslan ZL, Rao JS. Expression of cathepsin D during the progression of human gliomas. Neurosci Lett. 1996;208:171–174. PubMed

Lösch A, Schindl M, Kohlberger P, Lahodny J, Breitenecker G, Horvat R, et al. Cathepsin D in ovarian cancer: prognostic value and correlation with p53 expression and microvessel density. Gynecol Oncol. 2004;92:545–552. PubMed

González-Vela MC, Garijo MF, Fernández F, Buelta L, Val-Bernal JF. Cathepsin D in host stromal cells is associated with more highly vascular and aggressive invasive breast carcinoma. Histopathology. 1999;34:35–42. PubMed

Briozzo P, Badet J, Capony F, Pieri I, Montcourrier P, Barritault D, et al. MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: a permissive role of cathepsin D. Exp Cell Res. 1991;194:252–259. PubMed

Piwnica D, Fernandez I, Binart N, Touraine P, Kelly PA, Goffin V. A new mechanism for prolactin processing into 16K PRL by secreted cathepsin D. Mol Endocrinol. 2006;20:3263–3278. PubMed

Benes P, Vashishta A, Saraswat-Ohri S, Fusek M, Pospisilova S, Tichy B, et al. Effect of procathepsin D activation peptide on gene expression of breast cancer cells. Cancer Lett. 2006;239:46–54. PubMed

Fusek M, Vetvickova J, Vetvicka V. Secretion of cytokines in breast cancer cells: the molecular mechanism of procathepsin D proliferative effects. J Interferon Cytokine Res. 2007;27:191–199. PubMed

Ohri SS, Vashishta A, Vetvickova J, Fusek M, Vetvicka V. Procathepsin D expression correlates with invasive and metastatic phenotype of MDA-MB-231 derived cell lines. Int J Biol Macromol. 2007;41:204–209. PubMed

Vashishta A, Fusek M, Vetvicka V. Possible role of procathepsin D in human cancer. Folia Microbiol. 2005;50:71–76. PubMed

Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, et al. Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett. 2006;237:167–179. PubMed

Tumminello FM, Leto G, Gebbia N, Rausa L, Bernacki RJ. Evaluation of antitumor and antimetastatic activity of pepstatin A in some experimental tumor models. J Chemother. 1989;1:1135–1138. PubMed

Tumminello FM, Bernacki RJ, Gebbia N, Leto G. Pepstatins: aspartic proteinase inhibitors having potential therapeutic applications. Med Res Rev. 1993;13:199–208. PubMed

Leto G, Pizzolanti G, Tumminello FM, Gebbia N. Effects of E-64 (cysteine-proteinase inhibitor) and pepstatin (aspartyl-proteinase inhibitor) on metastasis formation in mice with mammary and ovarian tumors. In Vivo. 1994;8:231–236. PubMed

Agostinelli E, Seiler N. Lysosomotropic compounds and spermine enzymatic oxidation products in cancer therapy (Review) Int J Oncol. 2007;31:473–484. PubMed

Vetvicka V, Fusek M. Activation of peripheral blood neutrophils and lymphocytes by human procathepsin D and insulin-like growth factor II. Cell Immunol. 1994;156:332–341. PubMed

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