Xie Jie, Tao Zhong-Hua, Zhao Jiang, Li Ting, Wu Zheng-Hua, Zhang Jin-Feng, Zhang Jian, Hu Xi-Chun
Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong'an Road, Shanghai, 200032, China.
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong'an Road, Shanghai, 200032, China.
Biochem Biophys Res Commun. 2016 Jun 3;474(3):612-619. doi: 10.1016/j.bbrc.2016.03.002. Epub 2016 Mar 21.
The underlying mechanism of gemcitabine resistance during breast cancer treatment remains unclear. Glucose regulated protein 78 (GRP78) frequently triggered by anticancer agents, was substantially elevated in gemcitabine resistant sublines. Ectopic expression of GRP78 changes gemcitabine chemosensitivity and apoptosis levels in breast cancer cells. Further experiments showed an involvement of caspase 9, not caspase 8, in gemcitabine resistance and GRP78-mediated chemosensitivity, suggesting that mitochondria apoptotic pathway was activated by GRP78. This finding was further supported by the observations of AKT activation, Bcl-2 increase, Bax and Bim decrease. Conclusively, GRP78 plays a vital role in gemcitabine resistance and clinical strategy to improve gemcitabine efficacy in breast cancer by manipulating GRP78 should be explored.
乳腺癌治疗期间吉西他滨耐药的潜在机制仍不清楚。葡萄糖调节蛋白78（GRP78）经常由抗癌药物触发，在吉西他滨耐药亚系中显著升高。GRP78的异位表达改变了乳腺癌细胞对吉西他滨的化疗敏感性和凋亡水平。进一步的实验表明，吉西他滨耐药和GRP78介导的化疗敏感性涉及caspase 9而非caspase 8，这表明GRP78激活了线粒体凋亡途径。AKT激活、Bcl-2增加、Bax和Bim减少的观察结果进一步支持了这一发现。总之，GRP78在吉西他滨耐药中起重要作用，应探索通过调控GRP78提高乳腺癌吉西他滨疗效的临床策略。
