A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells.
A number of proteins involved in cell growth control, including members of the Ras family of GTPases, are modified at their C terminus by a three-step posttranslational process termed prenylation. The enzyme isoprenylcysteine carboxylmethyl-transferase (Icmt) catalyzes the last step in this process, and genetic and pharmacological suppression of Icmt activity significantly impacts on cell growth and oncogenesis. Screening of a diverse chemical library led to the identification of a specific small molecule inhibitor of Icmt, cysmethynil, that inhibited growth factor signaling and tumorigenesis in an in vitro cancer cell model (Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., and Casey, P. J. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 4336-4341). To further evaluate the mechanisms through which this Icmt inhibitor impacts on cancer cells, we developed both in vitro and in vivo models utilizing PC3 prostate cancer cells. Treatment of these cells with cysmethynil resulted in both an accumulation of cells in the G(1) phase and cell death. Treatment of mice harboring PC3 cell-derived xenograft tumors with cysmethynil resulted in markedly reduced tumor size. Analysis of cell death pathways unexpectedly showed minimal impact of cysmethynil treatment on apoptosis; rather, drug treatment significantly enhanced autophagy and autophagic cell death. Cysmethynil-treated cells displayed reduced mammalian target of rapamycin (mTOR) signaling, providing a potential mechanism for the excessive autophagy as well as G(1) cell cycle arrest observed. These results identify a novel mechanism for the antitumor activity of Icmt inhibition. Further, the dual effects of cell death and cell cycle arrest by cysmethynil treatment strengthen the rationale for targeting Icmt in cancer chemotherapy.
Wang
Mei
M
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore 169547.
Tan
Wanloo
W
Zhou
Jin
J
Leow
Jolene
J
Go
Meilin
M
Lee
How Sung
HS
Casey
Patrick J
PJ
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000178:diet therapy* / Q000201:enzymology; D011494:Protein Kinases / Q000378:metabolism; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D009363:Neoplasm Proteins; C530692:cysmethynil; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins