Le ciblage de la myoferline induit la mitophagie et amorce la ferroptose dans les cellules cancéreuses pancréatiques

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Myoferlin contributes to the metastatic phenotype of pancreatic cancer cells by enhancing their migratory capacity through the control of oxidative phosphorylation

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5%, and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness. Accordingly, understanding the mechanisms sustaining the PDAC metastatic phenotype remains a priority. In this study, we have generated and used a murine in vivo model to select clones from the human PANC-1 PDAC cell line that exhibit a high propensity to seed and metastasized into the liver. We showed that myoferlin, a protein previously reported to be overexpressed in PDAC, is significantly involved in the migratory abilities of the selected cells. We first report that highly PANC-1 metastatic clones expressed significantly higher myoferlin level than the corresponding low metastatic ones. Using scratch wound and Boyden’s chamber assays, we show that cells expressing high myoferlin level have higher migratory potential than cells characterized by a low myoferlin abundance. Moreover, we demonstrate that myoferlin silencing leads to a migration decrease associated to a reduction of mitochondrial respiration. Since mitochondrial oxidative phosphorylation has been shown to be implicated in the tumor progression and dissemination, our data identify myoferlin as a valid potential therapeutic target in PDAC

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460

Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response

peer reviewedPancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy

Improving pancreatic cancer response to gemcitabine by overcoming methylglyoxal driven suppression of AMPK

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