Impact of Extracellular pH on Apoptotic and Non-Apoptotic TRAIL-Induced Signaling in Pancreatic Ductal Adenocarcinoma Cells
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important mediator of tumor immune surveillance. In addition, its potential to kill cancer cells without harming healthy cells led to the development of TRAIL receptor agonists, which however did not show the desired effects in clinical trials. This is caused mainly by apoptosis resistance mechanisms operating in primary cancer cells. Meanwhile, it has been realized that in addition to cell death, TRAIL also induces non-apoptotic pro-in fl ammatory pathways that may enhance tumor malignancy. Due to its late detection and resistance to current therapeutic options, pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest types of cancer worldwide. A dysregulated pH microenvironment contributes to PDAC development, in which the cancer cells become highly dependent on to maintain their metabolism. The impact of extracellular pH (pH e ) on TRAIL-induced signaling in PDAC cells is poorly understood so far. To close this gap, we analyzed the effects of acidic and alkaline pH e , both in short-term and long-term settings, on apoptotic and non-apoptotic TRAIL-induced signaling. We found that acidic and alkaline pH e differentially impact TRAIL-induced responses, and in addition, the duration of the pH e exposition also represents an important parameter. Thus, adaptation to acidic pH e increases TRAIL sensitivity in two different PDAC cell lines, Colo357 and Panc1, one already TRAIL-sensitive and the other TRAIL-resistant, respectively. However, the latter became highly TRAIL-sensitive only by concomitant inhibition of Bcl-xL. None of these effects was observed under other pH e conditions studied.
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