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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