Carcinogenesis Advance Access originally published online on November 21, 2008
Carcinogenesis 2009 30(1):35-42; doi:10.1093/carcin/bgn251
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Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells
,*
Cancer Institute
1 Department of Gastroenterology, 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, China
* To whom correspondence should be addressed. Tel: +86 571 87783566; Fax: +86 571 87214404; Email: ylzhu{at}yahoo.cn
Overexpression of multidrug resistance proteins (Mdrs) and enhanced antiapoptotic 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 antiapoptosis capacity in the drug-resistant process needs to be further understood. Here, we identified human brain expressed X-linked 1 (hBex1) as a downstream target of the p75 neurotrophin receptor 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.
Abbreviations: ABC, adenosine triphosphate-binding cassette transport protein; ANOVA, analysis of variance; CML, chronic myeloid leukemia; FBS, fetal bovine serum; FCM, flow cytometry; GAPDH, glyceraldehyde-3-phosphate dehyrogenase; GFP, green fluorescent protein; hBex1, human brain expressed X-linked 1; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; Mdr, multidrug resistance protein; NF-
B, nuclear factor-kappa B; PCR, polymerase chain reaction; p75NTR, p75 neurotrophin receptor; PCDH10, protocadherin 10
These authors are co-corresponding author Received July 13, 2008; revised October 29, 2008; accepted November 1, 2008.