The effects of sarcosine on the processes driving prostate cancer (PCa) development remain still unclear. Herein, we show that a supplementation of metastatic PCa cells (androgen independent PC-3 and androgen dependent LNCaP) with sarcosine stimulates cells proliferation in vitro. Similar stimulatory effects were observed also in PCa murine xenografts, in which sarcosine treatment induced a tumor growth and significantly reduced weight of treated mice (p < 0.05). Determination of sarcosine metabolism-related amino acids and enzymes within tumor mass revealed significantly increased glycine, serine and sarcosine concentrations after treatment accompanied with the increased amount of sarcosine dehydrogenase. In both tumor types, dimethylglycine and glycine-N-methyltransferase were affected slightly, only. To identify the effects of sarcosine treatment on the expression of genes involved in any aspect of cancer development, we further investigated expression profiles of excised tumors using cDNA electrochemical microarray followed by validation using the semi-quantitative PCR. We found 25 differentially expressed genes in PC-3, 32 in LNCaP tumors and 18 overlapping genes. Bioinformatical processing revealed strong sarcosine-related induction of genes involved particularly in a cell cycle progression. Our exploratory study demonstrates that sarcosine stimulates PCa metastatic cells irrespectively of androgen dependence. Overall, the obtained data provides valuable information towards understanding the role of sarcosine in PCa progression and adds another piece of puzzle into a picture of sarcosine oncometabolic potential.

Central European Institute of Technology Brno University of Technology Purkynova 123 Brno CZ 612 00 Czech Republic

Department of Biochemistry Faculty of Science Charles University Albertov 2030 CZ 128 40 Prague 2 Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 CZ 150 06 Prague 5 Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 5 Brno CZ 625 00 Czech Republic

Department of Urology University Hospital Brno Jihlavska 20 Brno CZ 625 00 Czech Republic

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PLoS One. 2022 May 19;17(5):e0268981. doi: 10.1371/journal.pone.0268981. PubMed

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Cernei N, Heger Z, Gumulec J, Zitka O, Masarik M, Babula P, et al. Sarcosine as a Potential Prostate Cancer Biomarker-A Review. Int J Mol Sci. 2013;14(7):13893–908. 10.3390/ijms140713893 . PubMed DOI PMC

Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu JD, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910–4. 10.1038/nature07762 . PubMed DOI PMC

Heger Z, Cernei N, Gumulec J, Masarik M, Eckschlager T, Hrabec R, et al. Determination of common urine substances as an assay for improving prostate carcinoma diagnostics. Oncol Rep. 2014;31(4):1846–54. 10.3892/or.2014.3054 . PubMed DOI

Kumar D, Gupta A, Mandhani A, Sankhwar SN. Metabolomics-Derived Prostate Cancer Biomarkers: Fact or Fiction? J Proteome Res. 2015;14(3):1455–64. 10.1021/pr5011108 . PubMed DOI

Heger Z, Cernei N, Krizkova S, Masarik M, Kopel P, Hodek P, et al. Paramagnetic Nanoparticles as a Platform for FRET-Based Sarcosine Picomolar Detection. Sci Rep. 2015;5:1–7. 8868 10.1038/srep08868 . PubMed DOI PMC

Ankerst DP, Liss M, Zapata D, Hoefler J, Thompson IM, Leach RJ. A case control study of sarcosine as an early prostate cancer detection biomarker. BMC Urol. 2015;15:1–4. 99 10.1186/s12894-015-0095-5 . PubMed DOI PMC

Jentzmik F, Stephan C, Miller K, Schrader M, Erbersdobler A, Kristiansen G, et al. Sarcosine in Urine after Digital Rectal Examination Fails as a Marker in Prostate Cancer Detection and Identification of Aggressive Tumours. Eur Urol. 2010;58(1):12–8. 10.1016/j.eururo.2010.01.035 . PubMed DOI

Heger Z, Gumulec J, Cernei N, Polanska H, Raudenska M, Masarik M, et al. Relation of exposure to amino acids involved in sarcosine metabolic pathway on behavior of non-tumor and malignant prostatic cell lines. Prostate. 2016;76(7):679–90. 10.1002/pros.23159 . PubMed DOI

Sudhakaran PR, Binu S, Soumya SJ. Effect of sarcosine on endothelial function relevant to angiogenesis. J Canc Res Ther. 2014;10(3):603–10. 10.4103/0973-1482.137945 . PubMed DOI

Khan AP, Rajendiran TM, Ateeq B, Asangani IA, Athanikar JN, Yocum AK, et al. The Role of Sarcosine Metabolism in Prostate Cancer Progression. Neoplasia. 2013;15(5):491–501. 10.1593/neo.13314 . PubMed DOI PMC

Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8. 10.1038/35077213 . PubMed DOI

Geschwind DH. DNA microarrays: translation of the genome from laboratory to clinic. Lancet Neurol. 2003;2(5):275–82. 10.1016/s1474-4422(03)00379-x . PubMed DOI

Lipshutz RJ, Fodor SPA, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays. Nature Genet. 1999;21:20–4. 10.1038/4447 . PubMed DOI

Heger Z, Cernei N, Kudr J, Gumulec J, Blazkova I, Zitka O, et al. A Novel Insight into the Cardiotoxicity of Antineoplastic Drug Doxorubicin. Int J Mol Sci. 2013;14(11):21629–46. 10.3390/ijms141121629 . PubMed DOI PMC

Roth KM, Peyvan K, Schwarzkopf KR, Ghindilis A. Electrochemical detection of short DNA oligomer hybridization using the CombiMatrix ElectraSense Microarray reader. Electroanalysis. 2006;18(19–20):1982–8. 10.1002/elan.200603603 . DOI

Heger Z, Michalek P, Guran R, Havelkova B, Kominkova M, Cernei N, et al. Exposure to 17 beta-Oestradiol Induces Oxidative Stress in the Non-Oestrogen Receptor Invertebrate Species Eisenia fetida. PLoS One. 2015;10(12). e0145426 10.1371/journal.pone.0145426 . PubMed DOI PMC

Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M. KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res. 2010;38:D355–D60. 10.1093/nar/gkp896 . PubMed DOI PMC

Ding ZH, Wu CJ, Chu GC, Xiao YH, Ho D, Zhang JF, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470(7333):269–73. 10.1038/nature09677 . PubMed DOI PMC

Tomlins SA, Aubin SMJ, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, et al. Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA. Sci Transl Med. 2011;3(94). 94ra72 10.1126/scitranslmed.3001970 . PubMed DOI PMC

Heiden MGV, Cantley LC, Thompson CB. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science. 2009;324(5930):1029–33. 10.1126/science.1160809 . PubMed DOI PMC

Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13(8):572–83. 10.1038/nrc3557 . PubMed DOI PMC

Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends BiochemSci. 2014;39(4):191–8. 10.1016/j.tibs.2014.02.004 . PubMed DOI PMC

Brosnan ME, MacMillan L, Stevens JR, Brosnan JT. Division of labour: how does folate metabolism partition between one-carbon metabolism and amino acid oxidation? Biochem J. 2015;472:135–46. 10.1042/bj20150837 . PubMed DOI

Marchetti C, Palaia I, Giorgini M, De Medici C, Iadarola R, Vertechy L, et al. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. OncoTargets Ther. 2014;7:1223–36. 10.2147/ott.s40947 . PubMed DOI PMC

Yoon JK, Kim DH, Koo JS. Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer. J Transl Med. 2014;12 149 10.1186/1479-5876-12-149 . PubMed DOI PMC

Green T, Chen XF, Ryan S, Asch AS, Ruiz-Echevarria MJ. TMEFF2 and SARDH cooperate to modulate one-carbon metabolism and invasion of prostate cancer cells. Prostate. 2013;73(14):1561–75. 10.1002/pros.22706 . PubMed DOI PMC

Burdelski C, Strauss C, Tsourlakis MC, Kluth M, Hube-Magg C, Melling N, et al. Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer. Oncotarget. 2015;6(10):8377–87. 10.18632/oncotarget.3107 PubMed DOI PMC

Brody JR, Hucl T, Costantino CL, Eshleman JR, Gallmeier E, Zhu H, et al. Limits to Thymidylate Synthase and TP53 Genes as Predictive Determinants for Fluoropyrimidine Sensitivity and Further Evidence for RNA-Based Toxicity as a Major Influence. Cancer Res. 2009;69(3):984–91. 10.1158/0008-5472.can-08-3610 . PubMed DOI PMC

Park K, Chen ZM, MacDonald TY, Siddiqui J, Ye HH, Erbersdobler A, et al. Prostate cancer with Paneth cell-like neuroendocrine differentiation has recognizable histomorphology and harbors AURKA gene amplification. Hum Pathol. 2014;45(10):2136–43. 10.1016/j.humpath.2014.06.008 . PubMed DOI PMC

Zhou XJ, Zhang ZY, Yang X, Chen WT, Zhang P. Inhibition of cyclin D1 expression by cyclin D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin chemosensitivity. Int J Cancer. 2009;124(2):483–9. 10.1002/ijc.23964 . PubMed DOI

Mukai S, Yorita K, Yamasaki K, Nagai T, Kamibeppu T, Sugie S, et al. Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis. Hum Cell. 2015;28(3):133–42. 10.1007/s13577-015-0114-6 . PubMed DOI

Kote-Jarai Z, Al Olama AA, Leongamornlert D, Tymrakiewicz M, Saunders E, Guy M, et al. Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Hum Genet. 2011;129(6):687–94. 10.1007/s00439-011-0981-1 . PubMed DOI PMC

Wang HF, Gao X, Lu X, Wang Y, Ma CF, Shi ZK, et al. The mitotic regulator Hec1 is a critical modulator of prostate cancer through the long non-coding RNA BX647187 in vitro. Biosci Rep. 2015;35 e00273 10.1042/bsr20150003 . PubMed DOI PMC

Chen YM, Riley DJ, Zheng L, Chen PL, Lee WH. Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation. J Biol Chem. 2002;277(51):49408–16. 10.1074/jbc.M207069200 . PubMed DOI

Cooper CR, Graves B, Pruitt F, Chaib H, Lynch JE, Cox AK, et al. Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha. J Cell Biochem. 2008;104(6):2298–309. 10.1002/jcb.21785 . PubMed DOI

Deutsch AJA, Angerer H, Fuchs TE, Neumeister P. The Nuclear Orphan Receptors NR4A as Therapeutic Target in Cancer Therapy. Anti-Cancer Agents Med Chem. 2012;12(9):1001–14. . PubMed

Kim MJ, Jung WH, Koo JS. Expression of sarcosine metabolism-related proteins in estrogen receptor negative breast cancer according to the androgen receptor and HER-2 status. Int J Clin Exp Pathol. 2015;8(7):7967–77. . PubMed PMC

Dahl M, Bouchelouche P, Kramer-Marek G, Capala J, Nordling J, Bouchelouche K. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells. Mol Biol Rep. 2011;38(7):4237–43. 10.1007/s11033-010-0442-2 . PubMed DOI PMC

Tiwari N, Meyer-Schaller N, Arnold P, Antoniadis H, Pachkov M, van Nimwegen E, et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One. 2013;8(2). e57329 10.1371/journal.pone.0057329 . PubMed DOI PMC

Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signalling pathways in the regulation of cell survival. Faseb J. 2008;22(4):954–65. 10.1096/fj.06-7859rev . PubMed DOI

Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010;333(1–2):169–80. 10.1007/s11010-009-0217-z . PubMed DOI

Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8(4):253–67. 10.1038/nrc2347 . PubMed DOI

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