Cited by 77Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCell death mechanisms and regulation

Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth

Wang, M, Hossain, M S, Tan, W, Coolman, B, Zhou, J, Liu, S, Casey, P J·2010·Oncogene

Abstract

Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt), which catalyzes the final step in the post-translational C-terminal processing of prenylated proteins, suppresses tumor cell growth and induces cell death. Icmt inhibition by either a small molecule inhibitor termed as cysmethynil or inhibitory RNA induces marked autophagy leading to cell death. HepG2 cells were used to investigate the function of autophagy in tumor cell death. Suppression of autophagy, either pharmacologically or through knockdown of the autophagy essential proteins, Atg5 or Atg1, inhibits not only cysmethynil-induced autophagy, but also apoptosis in HepG2 cells. The dependence of cysmethynil-induced apoptosis on autophagy was further shown using autophagy-deficient mouse embryonic fibroblast (MEF) cells. Atg5(-/-) MEF cells were found to be resistant to cysmethynil-induced apoptosis, whereas wild-type MEFs showed high sensitivity to apoptosis induction. These data indicate that inhibition of Icmt can elicit cell death through two linked mechanisms, autophagy and apoptosis, and that autophagy can be an active player upstream of apoptosis in cell types capable of apoptotic cell death, such as HepG2 and MEFs. Further, treatment of mice-bearing HepG2-derived tumors with cysmethynil resulted in marked inhibition of tumor growth; analysis of tumor tissue from these mice revealed markers consistent with autophagy induction and cell growth arrest.

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Crossref · 10.1038/onc.2010.247

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  • Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines.

    “Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines [46–48].”

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Authors
Wang, M., Hossain, M. S., Tan, W., Coolman, B., Zhou, J., Liu, S., & Casey, P. J.
Affiliations
  • National University of Singapore (SG)
  • Duke Medical Center (US)
Corresponding author
Wang, M
Venue
Oncogene
Published
2010-07-12
Volume
29
Issue
35
Pages
4959-4970
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
OpenAlex
W1974673851
Cited by
75
References
51
Citations by year
2026: 1 · 2025: 2 · 2024: 8 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 9 · 2013: 5 · 2012: 2
FWCI
3.26
Type
journal article
Language
en
Open access
closed
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
autophagy, apoptosis, prenylated proteins, ATG5, Atg1, HepG2 cells, tumor growth inhibition, anticancer agents, mouse embryonic fibroblasts
MeSH terms
Autophagy-Related Protein 5, Animals, Autophagy, Cell Cycle, Enzyme Inhibitors, Fibroblasts, Humans, Indoles, Microtubule-Associated Proteins, Neoplasms, Protein Methyltransferases, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice

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