This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pan, J. Articles by Yeung, S.-C. J. Search for Related Content PubMed PubMed Citation Articles by Pan, J. Articles by Yeung, S.-C. J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB TAXOL Medline Plus Health Information Thyroid Cancer Related Collections Thyroid Endocrine Oncology

Bcl-2-Associated X Protein Is the Main Mediator of Manumycin A-Induced Apoptosis in Anaplastic Thyroid Cancer Cells

Departments of Experimental Therapeutics (J.P.), Thoracic and Cardiovascular Surgery (B. F.), General Internal Medicine, Ambulatory Treatment, and Emergency Care (H.H., L.S., S.-C.J.Y.), and Endocrine Neoplasia and Hormonal Disorders (S.-C.J.Y.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Sai-Ching Jim Yeung, Division of Internal Medicine, Unit 437, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: Dr. Yeung, syeung{at}mdanderson.org, or Dr. Pan, jpan{at}mdanderson.org.

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.

This article has been cited by other articles:

				D. Nahari, R. Satchi-Fainaro, M. Chen, I. Mitchell, L. B. Task, Z. Liu, J. Kihneman, A. B. Carroll, L. S. Terada, and F. E. Nwariaku Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer Mol. Cancer Ther., April 1, 2007; 6(4): 1329 - 1337. [Abstract] [Full Text] [PDF]