Original articles
Hong Zhang, Liyan Huang, Liyang Tao, Jianye Zhang, Fang Wang, Xu Zhang, Liwu Fu. Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 516-525

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression
Hong Zhanga, Liyan Huanga, Liyang Taoa, Jianye Zhangb, Fang Wanga, Xu Zhanga, Liwu Fua
a Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou 510060, China;
b School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
Abstract:
Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.
Key words:    Multidrug resistance    Secalonic acid D    Apoptosis    c-Jun    ABCG2   
Received: 2018-09-30     Revised:
DOI: 10.1016/j.apsb.2018.12.006
Funds: This work was supported by grants from the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" (No. 2018ZX09711002, China), Science and Technology Foundation of Guangdong Province (No. 2016A030312014, China), Guangzhou Science and Technology Program (No. 201707010048, China) and from the Scientific and Technological Leading Talent Project of Guangdong Province (2015, China).
Corresponding author: Liwu Fu     Email:Fulw@mail.sysu.edu.cn
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Hong Zhang
Liyan Huang
Liyang Tao
Jianye Zhang
Fang Wang
Xu Zhang
Liwu Fu

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