Bcl-2-associated X protein is the main mediator of manumycin a-induced apoptosis in anaplastic thyroid cancer cells.
We previously demonstrated that the combination of paclitaxel and manumycin A, a farnesyltransferase inhibitor, enhanced apoptosis of anaplastic thyroid cancer (ATC) cells. However, the mechanism of the manumycin-induced apoptosis is not fully understood. In this study, we discovered that mitochondrial ultrastructure condensation occurred after treatment with manumycin or manumycin plus paclitaxel. Bongkrekic acid and cyclosporin A, which are known inhibitors of the voltage-dependent anion channel, failed to inhibit cytochrome c release induced by manumycin or manumycin plus paclitaxel, suggesting that mitochondrial permeability transition pores were not involved. We also found that manumycin induced translocation of Bcl-2-associated X protein (Bax), another possible mediator of cytochrome c release, from the cytosol to the mitochondria. Silencing Bax with a specific small interfering RNA blocked manumycin-induced mitochondrial condensation and cytochrome c release, arguing the dependence of manumycin-induced apoptosis on Bax. Using a binary adenoviral vector system, we found that overexpression of Bax enhanced manumycin-induced apoptosis of ATC cells, and the combination of manumycin and overexpression of Bax increased inhibition of ATC xenograft growth in nude mice. Thus, we concluded that manumycin-induced apoptosis in ATC cells was primarily mediated by Bax and that increasing Bax expression may sensitize ATC cells to manumycin.
Pan
Jingxuan
J
Division of Internal Medicine, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Huang
Huizhi
H
Sun
Lily
L
Fang
Bingliang
B
Yeung
Sai-Ching Jim
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D017239:Paclitaxel / Q000633:toxicity; D011090:Polyenes / Q000633:toxicity*; D053284:Polyunsaturated Alkamides; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D014183:Transplantation, Heterologous; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C054474:manumycin; D017239:Paclitaxel