Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2010.247
Title: Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth
Authors: Wang, M. 
Hossain, M.S.
Tan, W. 
Coolman, B.
Zhou, J. 
Liu, S.
Casey, P.J. 
Keywords: apoptosis
autophagy
cancer therapy
farnesylation
isoprenylcysteine carboxylmethyltransferase (Icmt)
prenylation
Issue Date: 2-Sep-2010
Citation: Wang, M., Hossain, M.S., Tan, W., Coolman, B., Zhou, J., Liu, S., Casey, P.J. (2010-09-02). Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene 29 (35) : 4959-4970. ScholarBank@NUS Repository. https://doi.org/10.1038/onc.2010.247
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. © 2010 Macmillan Publishers Limited All rights reserved.
Source Title: Oncogene
URI: http://scholarbank.nus.edu.sg/handle/10635/110138
ISSN: 09509232
DOI: 10.1038/onc.2010.247
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