Perillyl alcohol induces c-Myc-dependent apoptosis in Bcr/Abl-transformed leukemia cells.
Bcr/Abl-transformed cells strongly resist apoptosis induced by most chemotherapy agents. However, in Bcr/Abl-transformed cells the monocyclic monoterpene, perillyl alcohol (POH), induces G0/G1 arrest and apoptosis without affecting Bcr/Abl expression or activity. The primary effect of POH is to cause growth arrest while apoptosis is a consequence of this arrest. Since Bcr/Abl induces constitutive expression of c-Myc, which is necessary for cell cycle transit from G1 into the S phase, we tested whether POH causes growth arrest by inhibiting expression of c-Myc. However, in POH-arrested Bcr/Abl-transformed cells, expression of c-Myc RNA and protein was not affected. Because expression of c-Myc during growth arrest can lead to apoptosis, we examined the role of c-Myc in POH-induced apoptosis. c-Myc induces expression of the ornithine decarboxylase (ODC) gene, which synthesizes polyamines that are necessary for cell growth. Myc-induced apoptosis operates through ODC and can be prevented with the ODC inhibitor, alpha-difluoromethylornithine (DFMO). We report that DFMO strongly protects cells from POH-induced apoptosis. These results show that in Bcr/Abl-transformed cells, POH activates a Myc-ODC apoptotic pathway that is not protected by the Bcr/Abl antiapoptotic mechanism.
Clark
Steven S
SS
Department of Human Oncology and Comprehensive Cancer Center, University of Wisconsin-Madison, 53792, USA. ssclark@wisc.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000518:Eflornithine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D065108:Ornithine Decarboxylase Inhibitors; D016196:S Phase / Q000187:drug effects; D014170:Transformation, Genetic
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D039821:Monoterpenes; D065108:Ornithine Decarboxylase Inhibitors; C032208:perillyl alcohol; D016044:Fusion Proteins, bcr-abl; D009955:Ornithine Decarboxylase; D000518:Eflornithine