Abstract
Pancreatic cancer remains one of the most difficult to treat human cancers despite recent advances in targeted therapy. Inhibition of isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that posttranslationally modifies a group of proteins including several small GTPases, suppresses proliferation of some human cancer cells. However, the efficacy of ICMT inhibition on human pancreatic cancer has not been evaluated. In this study, we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition. In these cells, ICMT suppression inhibited proliferation and induced apoptosis. This responsiveness to ICMT inhibition was confirmed in in vivo xenograft tumor mouse models using both a small-molecule inhibitor and shRNA-targeting ICMT. Mechanistically, we found that, in sensitive pancreatic cancer cells, ICMT inhibition induced mitochondrial respiratory deficiency and cellular energy depletion, leading to significant upregulation of p21. Furthermore, we characterized the role of p21 as a regulator and coordinator of cell signaling that responds to cell energy depletion. Apoptosis, but not autophagy, that is induced via p21-activated BNIP3 expression accounts for the efficacy of ICMT inhibition in sensitive pancreatic cancer cells in both in vitro and in vivo models. In contrast, cells resistant to ICMT inhibition demonstrated no mitochondria dysfunction or p21 signaling changes under ICMT suppression. These findings not only identify pancreatic cancers as potential therapeutic targets for ICMT suppression but also provide an avenue for identifying those subtypes that would be most responsive to agents targeting this critical enzyme. Mol Cancer Ther; 16(5); 914-23. ©2017 AACR.
Highlights
Pancreatic carcinomas are among the most difficult cancers to treat, and the 5-year survival rate remains as low as 5% [1]
We found that a subset of these cells are sensitive to Isoprenylcysteine carboxylmethyltransferase (ICMT) inhibition through the inhibition of mitochondria function and induction of an energy-depleted state, which results in the elevation of p21 and p21-dependent BNIP3 expression, leading to cell-cycle arrest and apoptosis
We provide a strong case for suppressing ICMT as a method to inhibit cell proliferation and induce cell death in pancreatic cancer cells
Summary
Pancreatic carcinomas are among the most difficult cancers to treat, and the 5-year survival rate remains as low as 5% [1]. Isoprenylcysteine carboxylmethyltransferase (ICMT) is the enzyme that catalyzes the last step of posttranslational prenylation-dependent modification of proteins. Most ICMT substrate proteins contain a C-terminal CAAX consensus motif. The carboxylmethylation by ICMT is essential for the proper function of CAAX proteins by regulating their subcellular localization, protein–protein interactions, and/or protein stability [2,3,4,5]. ICMT has shown promise as a therapeutic target, as suggested by genetic and inhibitor studies [6,7,8,9]. Recent investigations have indicated that inhibition of ICMT leads to metabolic disarray and suppres-
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