Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.

A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

“…Thus, by increasing the expression of pro-survival genes like Wwp2, myof, and sema3e, Sox9 likely promotes cellular survival during AKI. These genes are known to regulate phosphoinositide 3-kinase (PI3K)phosphatase and tensin homolog (PTEN) signaling (Wwp2) 48 , membrane and mitochondrial functions (Myoferlin) 49,50 , and cell death (Sema3e) 51 in nonrenal epithelial cells. Whether these genes regulate RTEC dysfunction and cell death in vivo through similar mechanisms remains unknown.…”

Transforming growth factor beta‐induced, an extracellular matrix interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration

“…Assessment of cell proliferation was performed as previously described . Briefly, 3 × 10 4 PANC‐1 cells were seeded in complete medium 48 hr after transfection.…”

“…Experiments were conducted in a Seahorse XFp extracellular flux analyzer (Agilent, Santa Clara, CA). Glycolysis stress test was performed on BxPC‐3, MiaPaCa‐2, PANC‐1 and HPAF‐II (1.5 × 10 4 cells/well) as previously described . The readout of the assay was extracellular acidification rate (ECAR, mpH/min).…”

Myoferlin, a multifunctional protein in normal cells, has novel and key roles in various cancers

“…Myoferlin depletion induces the phosphorylation of dynamin-related protein (DRP)-1 and increases its abundance, thus leading to mitochondrial fission and swelling. 39 Interestingly, depletion of myoferlin led to a reduction in autophagy induction. 39 The specific mechanisms may be mediated by blocking the receptor tyrosine kinases, inhibiting the secretions of matrix metalloproteinase and reversing the EMT process.…”

“…39 Interestingly, depletion of myoferlin led to a reduction in autophagy induction. 39 The specific mechanisms may be mediated by blocking the receptor tyrosine kinases, inhibiting the secretions of matrix metalloproteinase and reversing the EMT process. 69 Overall, myoferlin may provide a novel therapeutic target in PAC.…”