Abstract
ABT-737 is a BH3 mimetic small molecule inhibitor that can effectively inhibit the activity of antiapoptotic Bcl-2 family proteins including Bcl2, Bcl-xL and Bcl-w, and further enhances the effect of apoptosis by activating the proapoptotic proteins (t-Bid, Bad, Bim). In this study, we demonstrate that ABT-737 improved the radiation sensitivity of cervical cancer HeLa cells and thereby provoked cell apoptosis. Our results show that ABT-737 inhibited HeLa cell proliferation and activated JNK and its downstream target c-Jun, which caused the up-regulation of Bim expression. Blockade of JNK/c-Jun signaling pathway resulted in significant down-regulation of ABT-737-induced Bim mRNA and protein expression level. Also, ABT-737 could evoke the Bim promoter activity, and enhance the radiation sensitivity of HeLa cells via JNK/c-Jun and Bim signaling pathway. Our data imply that combination of ABT-737 and conventional radiation therapy might represent a highly effective therapeutic approach for future treatment of cervical cancer.
Highlights
Cervical cancer is the second most common cancer diagnosed in women besides breast cancer
Previous studies have shown that ABT737 participated in the apoptotic signaling pathway through inhibiting the function of Bcl-2/Bcl-xL, it could enhance apoptosis induced by JAK inhibition or Jun N-terminal kinase (JNK) activation. [2,3,4,5]
The purple solid product is solved in dimethyl sulfoxide (DMSO) and the absorbance of resultant purple solution is quantified by a spectrophotometer
Summary
Cervical cancer is the second most common cancer diagnosed in women besides breast cancer. The current conventional treatment for cervical cancer consists of surgery and radiation therapy. The use of radiation therapy started early this century, and it is still considered as the pre-eminent treatment for cervical cancer since it can be widely used in different stage of cervical cancer. Seeking a new path to improve the radiation sensitivity of cervical cancer cells will definitely provide the opportunity for achieving better prognosis of cervical cancer in the future. ABT-737 is a small molecule inhibitor mimicking the function of BH3-only protein (i.e. Bad). It binds to Bcl-xL and Bcl-2 (Ki#1 nmol/L) with high affinity at their hydrophobic grooves as antagonists, which disrupts the Bcl-2/Bax association and thereby provokes cell apoptosis [1].
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