scholarly journals Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3)

2018 ◽  
Vol 19 (9) ◽  
pp. 2750 ◽  
Author(s):  
Aneta Rogalska ◽  
Ewa Forma ◽  
Magdalena Bryś ◽  
Agnieszka Śliwińska ◽  
Agnieszka Marczak
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Energy Demand ◽  
Hypoxia Inducible Factor ◽  
Metabolic Stress ◽  
Ovarian Cancer Cells ◽  
Hypoxia Inducible Factor 1 ◽  
Cancer Cell Death ◽  
Chronic Hyperglycemia

Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell death. The aim of this study was to determine the cytotoxic efficiency of metformin on SKOV-3 cells cultured in hyperglycemia and normoglycemia. To identify the potential mechanism, we assessed the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA), as well as hypoxia-inducible factor 1-alpha (HIF1A) and glucose transporters (GLUT1, GLUT3). SKOV-3 cells were cultured in normoglycaemia (NG, 5 mM) and hyperglycemia (HG, 25 mM) with and without 10 mM metformin for 24, 48, and 72 h. The proliferation rate, apoptotic and necrotic SKOV-3 cell death were evaluated. Real-Time qPCR was employed to determine mRNA expression of OGT, OGA, GLUT1, GLUT3, and HIF1A. Metformin significantly reduced the proliferation of SKOV-3 cells under normal glucose conditions. Whereas, the efficacy of metformin to induce SKOV-3 cell death was reduced in hyperglycemia. Both hyperglycemia and metformin induced changes in the expression of genes involved in the O-GlcNAcylation status and HIF1A pathway. The obtained results suggest that dysregulation of O-GlcNAcylation, and the related HIF1A pathway, via hyperglycemia, is responsible for the decreased cytotoxic efficiency of metformin in human ovarian cancer cells.

scholarly journals RAS-related GTPases DIRAS1 and DIRAS2 induce autophagic cancer cell death and are required for autophagy in murine ovarian cancer cells

Autophagy ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. 637-653 ◽  
Author(s):  
Margie N. Sutton ◽  
Hailing Yang ◽  
Gilbert Y. Huang ◽  
Caroline Fu ◽  
Michael Pontikos ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Cancer Cell Death

scholarly journals Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2004
Author(s):  
Prabhu Thirusangu ◽  
Christopher L. Pathoulas ◽  
Upasana Ray ◽  
Yinan Xiao ◽  
Julie Staub ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Cathepsin L ◽  
Membrane Permeabilization ◽  
Apoptotic Cell Death ◽  
Ovarian Cancer Cells ◽  
Autophagic Flux

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

scholarly journals DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Benoît Thibault ◽  
Ludivine Genre ◽  
Augustin Le Naour ◽  
Clothilde Broca ◽  
Eliane Mery ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Ovarian Cancer Cells

scholarly journals Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic Cell Death in Human Ovarian Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (1) ◽  
pp. 207 ◽  
Author(s):  
Yi-Yue Wang ◽  
Jun Hyeok Kwak ◽  
Kyung-Tae Lee ◽  
Tsegaye Deyou ◽  
Young Pyo Jang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Millettia Ferruginea ◽  
Induced Apoptosis

The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3’,4’-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.

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