A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.

• Klíčová slova
• 4T1 cells, Anoikis resistance, Breast cancer, Ferroptosis, Metastasis, Reactive oxygen species,
• MeSH
• anoikis * účinky léků   genetika   MeSH
• benzhydrylové sloučeniny * farmakologie   MeSH
• ferroptóza * účinky léků   genetika   MeSH
• glifloziny farmakologie   MeSH
• glukosidy * farmakologie   MeSH
• kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prsu * patologie   metabolismus   farmakoterapie   genetika   MeSH
• peroxidace lipidů účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny * MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy * MeSH
• kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
• mikro RNA * MeSH
• MIRN128 microRNA, human MeSH Prohlížeč
• reaktivní formy kyslíku MeSH
• SLC34A2 protein, human MeSH Prohlížeč

Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of these cells has been shown to improve the health of aged experimental animals, leading to a clinical interest in finding compounds that selectively eliminate senescent cells while sparing non-senescent ones. In our study, we identified a senolytic capacity of statins, which are lipid-lowering drugs prescribed to patients at high risk of cardiovascular events. Using two different models of senescence in human vascular endothelial cells (HUVECs), we found that statins preferentially eliminated senescent cells, while leaving non-senescent cells unharmed. We observed that the senolytic effect of statins could be negated with the co-administration of mevalonic acid and that statins induced cell detachment leading to anoikis-like apoptosis, as evidenced by real-time visualization of caspase-3/7 activation. Our findings suggest that statins possess a senolytic property, possibly also contributing to their described beneficial cardiovascular effects. Further studies are needed to explore the potential of short-term, high-dose statin treatment as a candidate senolytic therapy.

• Klíčová slova
• anoikis, apoptosis, endothelial cells, senescence, senolytics, statins,
• MeSH
• anoikis MeSH
• endoteliální buňky MeSH
• léky proti stárnutí MeSH
• lidé MeSH
• senioři MeSH
• stárnutí buněk * MeSH
• statiny * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• léky proti stárnutí MeSH
• statiny * MeSH

Radiation and chemotherapy represent standard-of-care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio- and chemotherapy, we exposed human cancer cell lines (HeLa, MCF-7 and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low-adherent stem-like cells. Stress-mobilized low-adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in the development of a heterogeneous, low-adherent fraction comprising not only apoptotic/necrotic cells but also live cells exhibiting active Notch signalling and expressing stem-cell markers. Chemical inhibition of mitogen-activated protein kinase/ERK kinase (MEK) or siRNA-mediated knockdown of extracellular signal-regulated kinase 1/2 (Erk1/2) and interferon responsible factor 1 (IRF1) prevented mobilization of the surviving low-adherent population, indicating that interferon-gamma-mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF1. Notably, a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low-adherent cancer cells induced by 5-azacytidine or irradiation. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN suppressed the low-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively, implicating SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.

• Klíčová slova
• 5-azacytidine, cancer stem-like cells, interferon response, suprabasin, therapy-resistance,
• MeSH
• anoikis účinky léků   účinky záření   MeSH
• azacytidin farmakologie   MeSH
• chemorezistence MeSH
• diferenciační antigeny genetika   MeSH
• interferony farmakologie   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   účinky záření   MeSH
• nádorové proteiny genetika   MeSH
• nádory farmakoterapie   genetika   radioterapie   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   účinky záření   MeSH
• upregulace účinky léků   účinky záření   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• diferenciační antigeny MeSH
• interferony MeSH
• nádorové proteiny MeSH
• protinádorové látky MeSH
• SBSN protein, human MeSH Prohlížeč
• suprabasin protein, mouse MeSH Prohlížeč

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.

• MeSH
• anoikis MeSH
• buněčný rodokmen MeSH
• časové faktory MeSH
• chemokin CXCL12 metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• epitelové buňky účinky léků   metabolismus   patologie   MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• lymfocyty metabolismus   patologie   MeSH
• mezibuněčná komunikace MeSH
• myši transgenní MeSH
• myši MeSH
• nádorová transformace buněk genetika   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• nádorové mikroprostředí * MeSH
• nádory žaludku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nika kmenových buněk * MeSH
• protein Wnt 5a MeSH
• proteiny Wnt metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• receptory CXCR4 metabolismus   MeSH
• Rho proteiny vázající GTP metabolismus   MeSH
• rhoA protein vázající GTP MeSH
• signální dráha Wnt MeSH
• signální transdukce MeSH
• stárnutí buněk MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transplantace kostní dřeně MeSH
• žaludeční sliznice účinky léků   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BHLHA15 protein, human MeSH Prohlížeč
• Bhlha15 protein, mouse MeSH Prohlížeč
• chemokin CXCL12 MeSH
• Cxcl12 protein, mouse MeSH Prohlížeč
• CXCR4 protein, mouse MeSH Prohlížeč
• kadheriny MeSH
• protein Wnt 5a MeSH
• proteiny Wnt MeSH
• protinádorové látky MeSH
• receptory CXCR4 MeSH
• Rho proteiny vázající GTP MeSH
• rhoA protein vázající GTP MeSH
• RhoA protein, mouse MeSH Prohlížeč
• transkripční faktory bHLH MeSH
• Wnt5a protein, mouse MeSH Prohlížeč

The resistance of transformed epithelial cells to a detachment-induced apoptosis (anoikis) can significantly affect their susceptibility to anticancer therapy. We showed that detachment of both fetal (FHC) and adenocarcinoma (HT-29) human colon epithelial cells resulted in the activation of the pro-survival Akt pathway, and significant changes in integrin-linked kinase (ILK) and focal adhesive kinase (FAK) phosphorylation. We demonstrated a detachment-induced and PI3K/Akt-mediated resistance to apoptotic effects of TRAIL, which was not associated with any changes in the cell surface TRAIL death receptor levels. Instead, a modulation of downstream intracellular signaling events was suggested to be involved. Our results may have important implications for optimization of new strategies in treatment of cancers at different stages of development.

• MeSH
• adenokarcinom enzymologie   patologie   MeSH
• aktivace enzymů účinky léků   MeSH
• anoikis účinky léků   MeSH
• buněčná adheze účinky léků   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• buňky HT-29 MeSH
• chemorezistence účinky léků   MeSH
• epitelové buňky účinky léků   enzymologie   patologie   MeSH
• fokální adhezní tyrosinkinasy metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosforylace účinky léků   MeSH
• lidé MeSH
• nádory tračníku enzymologie   patologie   MeSH
• plod cytologie   MeSH
• protein TRAIL farmakologie   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• receptory domény smrti metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fokální adhezní tyrosinkinasy MeSH
• integrin-linked kinase MeSH Prohlížeč
• protein TRAIL MeSH
• protein-serin-threoninkinasy MeSH
• protoonkogenní proteiny c-akt MeSH
• receptory domény smrti MeSH

Nevocellular nevus can develop by two mechanisms: 1. after the chronic solar irradiation of the skin which impairs barrier lipids' homeostais and keratinocytes together with melanocytes undergo apoptosis; 2. Apoptosis can arise in melanocytes during phylogenetic development from the neural crest to epidermis when it migrates through the "enemy" territory of dermis. Apoptosis can be thus stopped by enzymatic process which results in anoikis and the endangered melanocyte would further proliferate. The later is the path of nevocellular nevi.

• MeSH
• anoikis fyziologie   MeSH
• apoptóza fyziologie   MeSH
• lidé MeSH
• melanocyty fyziologie   MeSH
• nádory kůže patofyziologie   MeSH
• pigmentový névus patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH