TRPM8 ion channel is aberrantly expressed and required for preventing replicative senescence in pancreatic adenocarcinoma

Abstract

Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.

TRPC6 in simulated microgravity of intervertebral disc cells

“…Therefore, TRPC6 could potentially be of importance in the progression of IVD degeneration linked to cell senescence, but further studies are needed. In fact, the role of TRP channels in modulating senescence is also known for other cell types, such as endothelial cells (TRPC5) [47], pancreatic adenocarcinoma cells (TRPM7, TRPM8) [48,49] and lung fibroblasts (TRPC6) [30].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…On a more positive note, in a second independent study, the combination of anti-TRPM7 siRNA and gemcitabine produced enhanced tumor cell killing compared with gemcitabine alone (Yee et al, 2012b). A subset of patients with pancreatic carcinoma aberrantly expresses TRPM8 (Yee et al, 2012a). Targeted inhibition of TRPM8 in these patients may increase survival.…”

“…In pancreatic ductal adenocarcinoma, TRPM7 (Rybarczyk et al, 2012) and TRPM8 (Yee et al, 2012a) have been identified as potential therapeutic targets. Compared with non-neoplastic pancreatic tissue, TRPM7 is highly expressed (13-fold) in pancreatic cancer.…”

Translating Discovery in Zebrafish Pancreatic Development to Human Pancreatic Cancer: Biomarkers, Targets, Pathogenesis, and Therapeutics

“…Small interfering RNA-mediated silencing of TRPM7 or TRPM8 reduces cellular proliferation, impairs cell cycle progression, and induces replicative senescence in the pancreatic cancer cells. 34,[45][46][47][48] These data further demonstrate the potential of human orthologs to developmental regulators of exocrine pancreas in zebrafish as clinical biomarkers and therapeutic targets in human pancreatic cancer. 47 …”

“…7A, B). Based on these study results, we discovered that TRPM7 and its subfamily member TRPM8 are aberrantly over-expressed in human pancreatic adenocarcinoma 34,[45][46][47] ( Fig. 7C, D).…”