TRPV6 Channel Is Involved in Pancreatic Ductal Adenocarcinoma Aggressiveness and Resistance to Chemotherapeutics

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatments and poor prognosis. TRPV6, a calcium-permeable channel overexpressed in cancers, holds potential as an influencer of cancer cell behavior. This study investigates TRPV6 expression in PDAC, analyzing 46 patient tissue samples of varying stages and grades. We manipulated TRPV6 expression (knockdown, overexpression) in the human PDAC cell lines Panc-1 and Capan-1. We then revealed the impact of TRPV6 expression on Ca2+ influx, proliferation, apoptosis, migration, chemoresistance, and tumor growth both in vitro and in vivo. Notably, TRPV6 expression correlated with tumor stage and grade, relating it to PDAC proliferation. Knockdown decreased Ca2+ influx. This was paralleled by reduced proliferation, enhanced apoptosis, and sensitization of cells to chemotherapeutic drugs. Conversely, TRPV6 overexpression yielded opposing effects. Strikingly, both knockdown and overexpression curtailed tumor formation in vivo. These findings underscore an intricate role of TRPV6 channels in PDAC progression, highlighting its potential as a therapeutic target.Abstract Pancreatic ductal adenocarcinoma (PDAC) stands as a highly aggressive and lethal cancer, characterized by a grim prognosis and scarce treatment alternatives. Within this context, TRPV6, a calcium-permeable channel, emerges as a noteworthy candidate due to its overexpression in various cancers, capable of influencing the cell behavior in different cancer entities. Nonetheless, the exact expression pattern and functional significance of TRPV6 in the context of PDAC remains enigmatic. This study scrutinizes the expression of TRPV6 in tissue specimens obtained from 46 PDAC patients across distinct stages and grades. We manipulated TRPV6 expression (knockdown, overexpression) in the human PDAC cell lines Panc-1 and Capan-1. Subsequently, we analyzed its impact on multiple facets, encompassing Ca2+ influx, proliferation, apoptosis, migration, chemoresistance, and tumor growth, both in vitro and in vivo. Notably, the data indicate a direct correlation between TRPV6 expression levels, tumor stage, and grade, establishing a link between TRPV6 and PDAC proliferation in tissue samples. Decreasing TRPV6 expression via knockdown hampered Ca2+ influx, resulting in diminished proliferation and viability in both cell lines, and cell cycle progression in Panc-1. The knockdown simultaneously led to an increase in apoptotic rates and increased the susceptibility of cells to 5-FU and gemcitabine treatments. Moreover, it accelerated migration and promoted collective movement among Panc-1 cells. Conversely, TRPV6 overexpression yielded opposing outcomes in terms of proliferation in Panc-1 and Capan-1, and the migration of Panc-1 cells. Intriguingly, both TRPV6 knockdown and overexpression diminished the process of tumor formation in vivo. This intricate interplay suggests that PDAC aggressiveness relies on a fine-tuned TRPV6 expression, raising its profile as a putative therapeutic target.