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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(3):544-551; doi:10.1093/carcin/bgm294
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Activation of the JNK pathway promotes phosphorylation and degradation of BimEL—a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia

Kam Tong Leung, Karen Kwai-Har Li1, Samuel Sai-Ming Sun, Paul Kay Sheung Chan2, Vincent Eng-Choon Ooi and Lawrence Chi-Ming Chiu*

Department of Biology, The Chinese University of Hong Kong, Hong Kong SAR, China
1 Department of Pediatrics
2 Department of Microbiology, Prince of Wales Hospital, Hong Kong SAR, China

* To whom correspondence should be addressed. Tel: +852-3163-4466; Fax: +852-2603-5745; Email: chimingchiu{at}graduate.hku.hk

T-cell acute lymphoblastic leukemias (T-ALLs) are highly malignant tumors with 20% of patients continues to fail therapy, in part due to chemoresistance of T-ALL cells via largely unknown mechanisms. Here, we showed that lack of Bcl-2-interacting mediator of cell death (Bim)EL protein expression, a BH3-only member of the Bcl-2 family proteins, conferred resistance of a T-ALL cell line, Sup-T1, to etoposide-induced apoptosis. Overexpression of BimEL significantly restored its sensitivity to etoposide-induced caspase activation and poly(ADP-ribose) polymerase cleavage. Surprisingly, we found that constitutive activation of the c-Jun N-terminal kinase (JNK) pathway in Sup-T1 cells promoted phosphorylation and degradation of BimEL via the proteosome. Blocking with a proteosome inhibitor yielded an elevated level of BimEL and accumulation of BimEL species phosphorylated at Ser69. Pretreatment of Sup-T1 cells with a specific JNK inhibitor, SP600125, also increased the BimEL level and resensitized the cells to etoposide-induced apoptosis. Together, our findings suggest that the JNK activation status may correlate with the BimEL level and in turn can control the sensitivity of T-ALL cells to chemotherapeutic agents.

Abbreviations: Bim, Bcl-2-interacting mediator of cell death; DEVD-AFC, N-acetyl-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; LEHD-AFC, N-acetyl-Leu-Glu-His-Asp-7-amino-4-trifluoromethyl coumarin; PARP, poly(ADP-ribose) polymerase; PCR, polymerase chain reaction; T-ALL, T-cell acute lymphoblastic leukemia; z-VAD-fmk, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

Received February 27, 2007; revised December 14, 2007; accepted December 15, 2007.


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