Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer

• Published in: Molecular cancer therapeutics 2017-05, Vol.16 (5), p.914-923
• Main Authors: Manu, Kanjoormana Aryan, Chai, Tin Fan, Teh, Jing Tsong, Zhu, Wan Long, Casey, Patrick J, Wang, Mei
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; BNIP3 protein; Cancer; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Depletion; Energy; Enzyme Inhibitors - administration & dosage; Enzymes; Gene Expression Regulation, Neoplastic - drug effects; Humans; Inhibition; Kinases; Membrane Proteins - genetics; Mice; Mitochondria; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phagocytosis; Protein Methyltransferases - antagonists & inhibitors; Protein Methyltransferases - genetics; Proteins; Proto-Oncogene Proteins - genetics; rho GTP-Binding Proteins - genetics; Signal Transduction - drug effects; Signaling; Small Molecule Libraries - administration & dosage; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0703

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 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 and 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. .