Farnesyltransferase inhibitors-induced autophagy: alternative mechanisms?
Farnesyltransferase inhibitors (FTIs) were designed to block the action of Ras oncoproteins which depend on posttranslational modification by adding a farnesyl isoprenoid membrane anchor. However, off-target actions are believed to account for most of their antitumor activity. We recently reported the induction of autophagy in cancer cells in a dose-dependent manner by FTIs. We observed similar results of autophagy in a panel of tumor cell lines for the three FTIs tested. Therefore, the induction of autophagy is very likely a pharmacological class effect of inhibition of farnesyltransferase. In this addendum, we discuss the possible mechanisms underlying the induction of autophagy by FTIs, including reactive oxygen species-, DNA damage- and Ras-mediated pathways as alternatives to Rheb-mediated regulation of mTOR and autophagy.
Pan
Jingxuan
J
Department of Pathophysiology, Sun Yat-Sen University Medical School, Guangzhou, PR China. jingx_pan@yahoo.com.cn
Song
Enlin
E
Cheng
Chao
C
Lee
Mong-Hong
MH
Yeung
Sai-Ching Jim
SC
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D051379:Mice; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D020559:Monomeric GTP-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse