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

Publication ,  Journal Article
Manu, KA; Chai, TF; Teh, JT; Zhu, WL; Casey, PJ; Wang, M
Published in: Mol Cancer Ther
May 2017

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.

Duke Scholars

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 2017

Volume

16

Issue

5

Start / End Page

914 / 923

Location

United States

Related Subject Headings

  • rho GTP-Binding Proteins
  • Xenograft Model Antitumor Assays
  • Small Molecule Libraries
  • Signal Transduction
  • Proto-Oncogene Proteins
  • Protein Methyltransferases
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Manu, K. A., Chai, T. F., Teh, J. T., Zhu, W. L., Casey, P. J., & Wang, M. (2017). Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer. Mol Cancer Ther, 16(5), 914–923. https://doi.org/10.1158/1535-7163.MCT-16-0703
Manu, Kanjoormana Aryan, Tin Fan Chai, Jing Tsong Teh, Wan Long Zhu, Patrick J. Casey, and Mei Wang. “Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer.Mol Cancer Ther 16, no. 5 (May 2017): 914–23. https://doi.org/10.1158/1535-7163.MCT-16-0703.
Manu, Kanjoormana Aryan, et al. “Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer.Mol Cancer Ther, vol. 16, no. 5, May 2017, pp. 914–23. Pubmed, doi:10.1158/1535-7163.MCT-16-0703.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 2017

Volume

16

Issue

5

Start / End Page

914 / 923

Location

United States

Related Subject Headings

  • rho GTP-Binding Proteins
  • Xenograft Model Antitumor Assays
  • Small Molecule Libraries
  • Signal Transduction
  • Proto-Oncogene Proteins
  • Protein Methyltransferases
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins