Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells.

Abstract

Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells. Our data showed that BIIB021 induced significant growth inhibition and apoptosis that was predominantly mediated by the mitochondrial pathway. BIIB021 also resulted in proteasomal degradation of BCR-ABL proteins. In addition to induction of apoptosis, we report for the first time that BIIB021 induced autophagic response as evidenced by the formation of autophagosome, increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, decreased p62 (SQSTM1) protein levels. Further study suggested that Akt-mTOR-Ulk1 signaling pathway was involved in BIIB021-triggered autophagy. Moreover, blocking autophagy using pharmacological inhibitor 3-methyladenine and bafilomycin A1 significantly enhanced cell death and apoptosis induced by BIIB021, indicating the cytoprotective role of autophagy in BIIB021-treated CML cells. Collectively, these data provide possible molecular mechanisms for the antileukemic effect of BIIB021 on imatinib-sensitive and -resistant CML cells and provide new insights into the future application of BIIB021 in the clinical treatment of CML.

• Authors: Wei He, Xiujin Ye, Xianbo Huang, Wen Lel, Liangshun You, Lei Wang, Xiaohui Chen, Wenbin Qian
• Journal: International journal of oncology (Int J Oncol) Vol. 48 Issue 4 Pg. 1710-20 (Apr 2016) ISSN: 1791-2423 [Electronic] Greece
• PMID: 26892093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Intracellular Signaling Peptides and Proteins
• Pyridines
• Imatinib Mesylate
• MTOR protein, human
• Autophagy-Related Protein-1 Homolog
• TOR Serine-Threonine Kinases
• ULK1 protein, human
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Autophagy
• Autophagy-Related Protein-1 Homolog (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Imatinib Mesylate (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
• Mice
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)