Karcinom prsu patří mezi nejčastější zhoubná onemocnění u žen. Signální dráha PI3K/Akt/mTOR hraje důležitou roli v řadě buněčných procesů podílejících se na proliferaci, metabolismu, buněčném růstu a přežití. Alterace této signální dráhy byly nalezeny u celé řady nádorů, včetně nádoru prsu. Konstitutivní aktivace PI3K/Akt/mTOR signální dráhy hraje klíčovou roli v patogenezi nádoru a rezistenci na konvenční terapii. V souvislosti s nově schválenou léčbou pomocí inhibitorů PI3K nabývá na významu i stanovení PIK3CA mutačního statusu jako prediktivního markeru léčebné odpovědi.

Breast cancer is one of the most common malignancies in women. The PI3K/Akt/mTOR signaling pathway plays an important role in several cellular processes involved in proliferation, metabolism, cell growth, and survival. Alterations in this signaling pathway have been found in a variety of tumors, including breast cancer. Constitutive activation of the PI3K/Akt/mTOR signaling pathway plays a key role in tumor pathogenesis and resistance to conventional therapy. In connection with the newly approved treatment with PI3K inhibitors, the determination of PIK3CA mutation status as a predictive marker is also gaining in importance.

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• cílená molekulární terapie * MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

β -catenin signaling is required for hair follicle deve lopment and regeneration which are involved in the resuscitation of hair follicle stem cells (HFSCs). To further characterize the role of β -catenin in the regulation of proliferation of HFSCs, the β -catenin expression was measured in the defined stages of hair follicle cycle and the proliferative potency was determined by using an in vitro cell growth assay. Our results showed that activation of β -catenin correlated with HFSCs proliferation, which appeared to be mediated by the nuclear translocation of stabilized β -catenin and the activation of responsib le cell cycle genes (cyclin D1 and p21). In addition, PI3K/Akt pathway was also involved in the HFSCs proliferation, partly regulated by β -catenin signaling pathway. These results demonstrate that β -catenin is an essential factor in the regulation of HFSCs proliferation via PI3K/Akt pathway and might be a potential therapeutic target for the regulation of the yield of keratinocytes from HFSCs.

• Klíčová slova
• PI3K/Akt,
• MeSH
• beta-katenin * MeSH
• cyklin D1 MeSH
• fosfatidylinositol-3-kinasy MeSH
• imunohistochemie MeSH
• jaderné proteiny MeSH
• kmenové buňky * MeSH
• krysa rodu rattus MeSH
• onkogenní protein p21(ras) MeSH
• proliferace buněk MeSH
• transkripční faktory MeSH
• vlasový folikul * metabolismus   růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. L-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion and/or activation of the PI3K/Akt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTEN/PI3K/Akt signaling.

• MeSH
• asparaginasa * farmakologie   terapeutické užití   MeSH
• dítě MeSH
• fosfatidylinositol-3-kinasy * genetika   metabolismus   MeSH
• fosfohydroláza PTEN * genetika   metabolismus   MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk * farmakoterapie   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce MeSH
• T-lymfocyty metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Aberrant glycosylation, which impairs recognition capability of NK cells or modifies recognition pattern of target cells, is associated with cancer. Synthetic glycoconjugates (GCs), which modulate cell glycosylation, increase the sensitivity of tumor cells to therapy or boost anti-cancer immune response. In the current study, we employed N-acetyl-D-glucosamine-calix[4]arene (GN4C) as a modulator of cell glycosylation of NK cells represented by the NK-92 cell line and fresh human NK cells. For the first time, we have demonstrated that calix[4]arene-based GC down-regulated the expression of glycosyltransferases MGAT3 and MGAT5 in NK-92 and fresh NK cells. GN4C increased the susceptibility of tumor cells to cytotoxicity by purified fresh NK cells or NK-92 cells. This functional activation of NK cells and the NK-92 cell line correlated with an increased expression of NKG2D mRNA. In the NK-92 cell line, GN4C induced the synthesis of IL-2, IFN-gamma and tumor necrosis factor-alpha as well. Cellular signaling triggered by GN4C engaged PI3-kinase/ERK but not phospholipase C-gamma/JNK pathways. Simultaneously, in transformed NK-92 cells, GN4C reduced the rate of proliferation and down-regulated the c-MYC, EGF-receptor 1 and REL-A molecules. In conclusion, the modulation of glycosyltransferases MGAT3 and MGAT5 by synthetic GN4C correlated with the improvement of NK cell effector functions and the augmentation of tumor cells sensitivity to NK cell-mediated cytotoxicity.

• MeSH
• acyltransferasy imunologie   metabolismus   MeSH
• aktivace lymfocytů imunologie   MeSH
• buněčné linie MeSH
• buňky HT-29 MeSH
• buňky NK imunologie   metabolismus   MeSH
• cytotoxicita imunologická genetika   imunologie   MeSH
• exprese genu MeSH
• fosfatidylinositol-3-kinasy imunologie   metabolismus   MeSH
• glykokonjugáty imunologie   metabolismus   MeSH
• glykosylace MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• N-acetylglukosaminyltransferasy imunologie   metabolismus   MeSH
• nádory genetika   imunologie   metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk MeSH
• proteiny nervové tkáně imunologie   metabolismus   MeSH
• průtoková cytometrie MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• separace buněk MeSH
• signální transdukce imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The phosphatidylinositol 3‐kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.

• Publikační typ
• dopisy MeSH

Ruminants are often fed a high-concentrate (HC) diet to meet lactating demands, yet long-term concentrate feeding induces subacute ruminal acidosis (SARA) and leads to a decrease in milk fat. Buffering agent could enhance the acid base buffer capacity and has been used to prevent ruminant rumen SARA and improve the content of milk fat. Therefore, we tested whether a buffering agent increases lipid anabolism in the livers of goats and influences of milk fat synthesis. Twelve Saanen-lactating goats were randomly assigned to two groups: one group received a HC diet (Concentrate: Forage=60:40, Control) and the other group received the same diet with a buffering agent added (10 g sodium butyrate, C(4)H(7)NaO(2); 10 g sodium bicarbonate, NaHCO(3); BG) over a 20-week experimental period. Overall, milk fat increase (4.25+/-0.08 vs. 3.24+/-0.10; P<0.05), and lipopolysaccharide levels in the jugular (1.82+/-0.14 vs. 3.76+/-0.33) and rumen fluid (23,340+/-134 vs. 42,550+/-136) decreased in the buffering agent group (P<0.05). Liver consumption and release of nonesterified fatty acid (NEFA) into the bloodstream increased (P<0.05). Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and ribosomal protein S6 kinase (p70S6K) up-regulated significantly in the livers of the buffering agent group (P<0.05). It also up-regulated expression of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) and its downstream targets involved in fatty acid synthetic, including fatty acid synthetase (FAS), stearoyl-CoA desaturase (SCD-1) and acetyl-CoA carboxylase 1 (ACC1) (P<0.05). The BG diet increased insulin levels in blood (19.43+/-0.18 vs. 13.81+/-0.10, P<0.05), and insulin receptor was likewise elevated in the liver (P<0.05). Cumulatively, the BG diet increased plasma concentrations of NEFA by INS-PI3K/AKTSREBP-1c signaling pathway promoting their synthesis in the liver. The increased NEFA concentration in the blood during BG feeding may explain the up-regulated in the milk fat of lactating goats.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• inzulin farmakologie   MeSH
• kozy MeSH
• laktace účinky léků   metabolismus   MeSH
• metabolismus lipidů účinky léků   fyziologie   MeSH
• náhodné rozdělení MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• pufry MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Interleukin-22 (IL-22) is a pro-inflammatory cytokine released during the immune response in chronic liver injury. Although IL-22 mediates tissue regeneration, its uncontrolled production may generate a carcinogenic environment resulting in hepatocellular carcinoma (HCC). This study aims to identify the effect of IL-22 on anti-apoptotic and metastatic genes and the molecular pathways responsible for IL-22-mediated hepatic carcinogenesis. METHODS AND RESULTS: Three cancerous liver lines, HepG2, SNU-387, Huh7, and one normal liver line, THLE2, were treated with IL-22. RT-qPCR analysis was conducted to study the role of IL-22 in altering the expression levels of anti-apoptotic genes, MCL-1 and BCL-2, and metastatic genes, MMP-7 and MMP-9. A significant increase in expression levels of these genes was observed after IL-22 treatment. Furthermore, to explore the major pathways involved in IL-22-mediated upregulation of anti-apoptotic and metastatic genes, cells were treated with inhibitors of JAK/STAT and PI3K/AKT pathways along with IL-22. Resultantly, a significant decrease in expression levels of target genes was observed, indicating the involvement of JAK/STAT and PI3K/AKT signaling cascades in IL-22-mediated oncogenesis. Finally, Cell Scratch assay was performed to check the effect of IL-22 and inhibitors of JAK/STAT and PI3K/AKT on the metastatic potential of liver cells. While migration was observed in Huh7 and THLE2 cells treated with IL-22, no migration was observed in cells treated with IL-22 along with JAK/STAT and PI3K/AKT inhibitors. Results indicate that IL-22 encourages metastasis in HCC cells via the JAK/STAT and PI3K/AKT pathways. CONCLUSION: Results showed that IL-22 upregulates anti-apoptotic and metastatic genes in HCC through JAK/STAT and PI3K/AKT signaling pathways.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• hepatocelulární karcinom * metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory jater * metabolismus   MeSH
• proliferace buněk genetika   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW: The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.

• MeSH
• flavonoidy MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• glukosa metabolismus   MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• signální transdukce MeSH
• transkripční faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer.

• MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• glykolýza genetika   MeSH
• IGFBP-3 genetika   metabolismus   MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * genetika   MeSH
• proliferace buněk MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH