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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1246-1255. Prepublished online as a Blood First Edition Paper on September 23, 2004; DOI 10.1182/blood-2004-05-2041. This Article Full Text (PDF) All Versions of this Article: 2004-05-2041v1 105/3/1246    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Guo, F. Articles by Bhalla, K. Search for Related Content PubMed PubMed Citation Articles by Guo, F. Articles by Bhalla, K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 1, 2004 Accepted September 15, 2004 Mechanistic role of heat shock protein 70 in Bcr-Abl mediated resistance to apoptosis in human acute leukemia cells Fei Guo, Celia Sigua, Purva Bali, Prince George, Warren Fiskus, Anna Scuto, Srinivas Annavarapu, Abdelmoughite Mouttaki, Gautam Sondarva, Sheng Wei, Jie Wu, Julie Djeu, and Kapil Bhalla* Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA * Corresponding author; email: bhallakn{at}moffitt.usf.edu. Bcr-Abl expressing primary or cultured leukemia cells display high levels of the antiapoptotic heat shock protein (hsp) 70, and are resistant to cytarbine (Ara-C), etoposide or Apo-2L/TRAIL-induced apoptosis. Conversely, a stable expression of the cDNA of hsp70 in the reverse orientation attenuated not only hsp70 but also STAT5 and Bcl-xL levels. This increased apoptosis induced by cytarabine, etoposide or Apo-2L/TRAIL. Ectopic expression of hsp70 in HL-60 cells (HL-60/hsp70) inhibited Ara-C and etoposide-induced Bax conformation change and translocation to the mitochondria, attenuated the accumulation of cytochrome c, Smac and Omi/HtrA2 in the cytosol, as well as inhibited the processing and activity of caspase-9 and caspase-3. Hsp70 was bound to death receptors 4 and 5 (DR4 and DR5), and inhibited Apo-2L/TRAIL-induced assembly and activity of the death inducing signaling complex (DISC). HL-60/hsp70 cells exhibited increased levels and DNA binding activity of STAT5, which was associated with high levels of Pim-2 and Bcl-xL, and resistance to apoptosis. Expression of the dominant negative (DN) STAT5 re-sensitized HL-60/hsp70 cells to cytarbine, etoposide and Apo-2L/TRAIL induced apoptosis. Collectively, these findings suggest that hsp70 inhibits apoptosis upstream and downstream of the mitochondria, and is a promising therapeutic target for reversing drug-resistance in CML-BC and AML cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Is hsp70 another target for Ph+ leukemias? Gert Ossenkoppele Blood 2005 105: 917. [Full Text] [PDF] This article has been cited by other articles: T. Yoshida, Y. Zhang, L. A. Rivera Rosado, and B. Zhang Repeated Treatment with Subtoxic Doses of TRAIL Induces Resistance to Apoptosis through Its Death Receptors in MDA-MB-231 Breast Cancer Cells Mol. Cancer Res., November 1, 2009; 7(11): 1835 - 1844. [Abstract] [Full Text] [PDF] V Dudeja, S M Vickers, and A K Saluja The role of heat shock proteins in gastrointestinal diseases Gut, July 1, 2009; 58(7): 1000 - 1009. [Abstract] [Full Text] [PDF] M. Bots and R. W. Johnstone Rational Combinations Using HDAC Inhibitors Clin. 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Grant Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation Clin. Cancer Res., July 15, 2007; 13(14): 4280 - 4290. [Abstract] [Full Text] [PDF] C. Peng, J. Brain, Y. Hu, A. Goodrich, L. Kong, D. Grayzel, R. Pak, M. Read, and S. Li Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells Blood, July 15, 2007; 110(2): 678 - 685. [Abstract] [Full Text] [PDF] C.-C. Kuo, C.-M. Liang, C.-Y. Lai, and S.-M. Liang Involvement of Heat Shock Protein (Hsp)90beta but Not Hsp90{alpha} in Antiapoptotic Effect of CpG-B Oligodeoxynucleotide J. Immunol., May 15, 2007; 178(10): 6100 - 6108. [Abstract] [Full Text] [PDF] M. Wetzler, J. C. Earp, M. T. Brady, M. K. Keng, and W. J. 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