Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm294
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Activation of the JNK pathway promotes phosphorylation and degradation of BimEL – a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia
1 Department of Biology, The Chinese University of Hong Kong, Hong Kong SAR, China
2 Departmment of Pediatrics
3 Departmment of Microbiology, Prince of Wales Hospital, Hong Kong SAR, China
* To whom correspondence should be addressed. E-mail: 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 BimEL 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 PARP cleavage. Surprisingly, we found that constitutive activation of the 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.
Received February 27, 2007; revised December 14, 2007; accepted December 15, 2007.