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Carcinogenesis Advance Access published online on November 21, 2008
Carcinogenesis, doi:10.1093/carcin/bgn251
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of apoptosis by down-regulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells

Kefeng Ding1, Yanyan Su1, Lingrong Pang1, Qinghua Lu1, Zhanhuai Wang1, Suzhan Zhang1, Shu Zheng1, Jianshan Mao2,3 and Yongliang Zhu2,3

1 Cancer Institute
2 Gastroenterological Department, Education Ministry Key Laboratory of Cancer Prevention and Intervention, Second Affiliated Hospital of Zhejiang University School of Medicine. Jiefang road 88#, Hangzhou, Zhejiang province, PR China, 310009
3 Co-corresponding author. Correspondence to: Dr. Yongliang Zhu, Gastroenterological Department, Education Ministry Key Laboratory of Cancer Prevention and Intervention, Second Affiliated Hospital of Zhejiang University School of Medicine. Jiefang road 88#, Hangzhou, Zhejiang province, PR China, 310009. Tel: 86-571-87783566, Fax: 86-571-87214404, e-mail: ylzhu{at}yahoo.cn

Overexpression of multidrug resistance proteins (Mdr) and enhanced anti-apoptotic capability are two of the main mechanisms by which Bcr/Abl+ chronic myeloid leukemia cells acquire drug resistance; however, it has been shown that Mdr-1 expression provides minimal protection against cell apoptosis induced by chemotherapeutic drugs. The mechanism by which cells acquire an enhanced anti-apoptosis capacity in the drug-resistant process needs to be further understood. Here, we identified hBex1 as a downstream target of the p75 NTR pathway in imatinib-resistant K562 cells by comparing the gene expression profiles with the parent K562 cells. Silencing hBex1 inhibited imatinib-induced cell apoptosis and overexpression of hBex1 sensitized cells to imatinib-induced apoptosis. Further investigation revealed that hBex1 associates with protocadherin 10 (PCDH10). Silencing of pcdh10 attenuated apoptosis induced by imatinib in hBex1-transfected cells, suggesting that, in addition to Mdr and Bcl-2 family members, reduced expression of hBex1 can also inhibit imatinib-induced apoptosis. These data provide evidence that expression of hBex1 in leukemic cells is a novel mechanism by which chemoresistance is achieved and suggests that hBex1 is a potential molecular target for the development of novel leukemia treatments.

Key Words: chronic myeloid leukemia • chemoresistance • apoptosis • hBex1 • PCDH10

Received July 13, 2008; revised October 29, 2008; accepted November 1, 2008.


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