IMB-6G, a novel N-substituted sophoridinic acid derivative, induces endoplasmic reticulum stress-mediated apoptosis via activation of IRE1α and PERK signaling
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Na Zhang1, Chongwen Bi1, Lu Liu1, Yueying Dou1, Sheng Tang1, Weiqiang Pang1, Hongbin Deng1, Danqing Song1
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Hongbin Deng, e-mail: email@example.com
Danqing Song, e-mail: firstname.lastname@example.org
Keywords: sophoridinic acid, ER stress, apoptosis, hepatocellular carcinoma, CHOP
Received: October 11, 2015 Accepted: March 04, 2016 Published: March 18, 2016
Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which precede induction of apoptosis. Further study showed IMB-6G activated IRE1α and PERK pathways but did not stimulated ATF6 pathway in HCC cells. Moreover, silencing of IRE1α dramatically abrogated IMB-6G-induced pro-apoptotic ASK1-JNK signaling. Importantly, interruption of CHOP rendered HCC cells sensitive to IMB-6G-induced apoptosis via inactivation of Bim, PUMA and Bax. Thus, the IRE1α-ASK1 and PERK-CHOP pathways may be a novel molecular mechanism of IMB-6G-induced apoptosis. Collectively, our study demonstrates that IMB-6G induces ER stress-mediated apoptosis by activating IRE1α and PERK pathways. Our findings provide a rationale for the potential application of IMB-6G in HCC therapy.
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