Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells.

Abstract

The boronic acid dipeptide bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome and shows significant therapeutic efficacy in multiple myeloma. However, recent studies suggest that bortezomib may have more complex mechanisms of action in treating cancer. We report here that the endocytosis and lysosomal degradation of the receptor tyrosine kinase C-KIT are required for bortezomib- but not tyrosine kinase inhibitor imatinib-caused apoptosis of t(8;21) leukemia and gastrointestinal stromal tumor cells, suggesting that C-KIT may recruit an apoptosis initiator. We show that C-KIT binds and phosphorylates heat shock protein 90β (Hsp90β), which sequestrates apoptotic protease activating factor 1 (Apaf-1). Bortezomib dephosphorylates pHsp90β and releases Apaf-1. Although the activated caspase-3 is not sufficient to cause marked apoptosis, it cleaves the t(8;21) generated acute myeloid leukemia 1-eight twenty one (AML1-ETO) and AML1-ETO9a fusion proteins, with production of cleavage fragments that perturb the functions of the parental oncoproteins and further contribute to apoptosis. Notably, bortezomib exerts potent therapeutic efficacy in mice bearing AML1-ETO9a-driven leukemia. These data show that C-KIT-pHsp90β-Apaf-1 cascade is critical for some malignant cells to evade apoptosis, and the clinical therapeutic potentials of bortezomib in C-KIT-driven neoplasms should be further explored.

• Authors: Hai-Tong Fang, Bo Zhang, Xiao-Fen Pan, Li Gao, Tao Zhen, Hong-Xia Zhao, Liang Ma, Jun Xie, Zi Liu, Xian-Jun Yu, Xin Cheng, Ting-Ting Feng, Feng-Xiang Zhang, Yong Yang, Zhong-Guo Hu, Guo-Qing Sheng, Yong-Long Chen, Sai-Juan Chen, Zhu Chen, Guang-Biao Zhou
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 7 Pg. 2521-6 (Feb 14 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22308476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• Pyrazines
• Bortezomib
• Proto-Oncogene Proteins c-kit

Topics

• Apoptosis
• Boronic Acids (pharmacology)
• Bortezomib
• Chromosomes, Human, Pair 21
• Chromosomes, Human, Pair 8
• Humans
• Leukemia (genetics, pathology)
• Phosphorylation
• Protein Binding
• Proto-Oncogene Proteins c-kit (metabolism)
• Pyrazines (pharmacology)
• Translocation, Genetic