pH and TRAIL receptors interplay in pancreatic ductal adenocarcinoma cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly life-threatening type of cancer. Altered extracellular and intracellular pH (pHe and pHi) has become a common hallmark of cancer, with pHe being particularly acidic. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can bind to its two plasma membrane-bound death receptors, TRAIL-R1 and TRAIL-R2, and induce apoptosis in tumor cells while sparing healthy cells. This led to the development of TRAIL/TRAIL-R-based therapeutic drugs. Unfortunately, clinical trials have shown disappointing outcomes since tumor cells often develop TRAIL resistance mechanisms. This study sought to understand the interplay between the pH microenvironment and TRAIL-induced signaling in PDAC. Acid-adaptation increased TRAIL sensitivity in the TRAIL-sensitive cell line Colo357, whereas Panc1 cells were barely affected. PDAC cells maintained TRAIL resistance presumably through (1) decreased levels of TRAIL-R1 and cell surface expression of TRAIL-R1 and TRAIL-R2 after acid-adaptation. Secondly (2), apparent differences and changes in TRAIL-induced signaling pathways, like the pro-apoptotic and pro-inflammatory as well as in the levels of anti-apoptotic proteins, were observed in the two PDAC cell lines. Thirdly (3), acid-adapted Panc1 cells could be sensitized to TRAIL by using an inhibitor (Navitoclax) of Bcl-xL, proving the importance of the mitochondrial amplification loop in (Type II) PDAC cells. Fourthly (4), Panc1 cells showed higher pHi values than Colo357 cells. (5) Increased NHE1, MCT4, and CAIX levels in Panc1 cells compared to Colo357 cells upon acid-adaptation supported their differences in pHi regulation. (6) Lowering TRAIL-R1 levels can alter interactions between TRAIL-R2 and TRAIL-R4, which may influence pHi and cell survival. (7) Acid extruders may be essential in maintaining or inducing TRAIL resistance in PDAC