Dual effects of gossypol on human hepatocellular carcinoma via endoplasmic reticulum stress and autophagy
Dual effects of gossypol on human hepatocellular carcinoma via endoplasmic reticulum stress and autophagy
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棉酚通过内质网应激和自噬对人肝细胞癌的双重作用
DOI：
10.1016/j.biocel.2019.05.012
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发表时间：
2019
影响因子：
4
通讯作者：
Jiang Chunping
中科院分区：
文献类型：
--
作者：
Zhang Guang;Wang Zhongxia;Chen Weibo;Cao Yin;Wu Junyi;Qiang Guanghui;Ji Anlai;Wu Junhua;Jiang Chunping
肝细胞癌（HCC）的治疗效果仍不令人满意，迫切需要有效的新治疗方法。棉酚已被证明具有抗肝癌作用，但其潜在机制需要进一步研究。本研究发现棉酚在体内外均能抑制肝癌细胞的生长。肝癌细胞中诱导典型的凋亡。电镜观察到内质网和自噬体扩张，未折叠蛋白反应和自噬标记物的激活表明棉酚诱导内质网应激和自噬。C/EBP同源蛋白是导致细胞凋亡的关键因素，肌醇需要酶1α和真核起始因子2α起保护作用。自噬保护细胞免于ER应激相关的凋亡。体内外研究均表明，抑制自噬可增强棉酚的抗肝癌作用。总之，内质网应激是棉酚诱导细胞凋亡和自噬的分子机制。棉酚主要通过激活细胞凋亡而表现出抗肝癌活性。然而，棉酚诱导的自噬保护HCC细胞免受ER应激。因此，棉酚和自噬抑制剂的联合治疗可能会增强抗HCC的效果。
Treatment outcomes for hepatocellular carcinoma (HCC) remain unsatisfactory, and effective new therapeutic methods are urgently needed. Gossypol has been shown to have an anti-HCC effect, but the underlying mechanism requires further study. In this study, we found gossypol inhibited HCC cells in vitro and in vivo. Typical apoptosis was induced in HCC cells. Dilated ER and autophagosomes were observed by electron microscopy, and the activation of the unfolded protein response and autophagy markers suggested that gossypol induced both ER stress and autophagy. C/EBP homologous protein was the key factor that led to apoptotic cell death, whereas inositol-requiring enzyme 1α and eukaryotic initiation factor 2α played a protective role. Autophagy protected the cells from ER stress-related apoptosis. Both in vitro and in vivo studies indicated that inhibition of autophagy enhanced the anti-HCC effect of gossypol. Taken together, ER stress is the molecular mechanism underlying gossypol-induced apoptosis and autophagy. Gossypol exhibits anti-HCC activity primarily through the activation of apoptosis. However, gossypol-induced autophagy protects HCC cells from ER stress. Therefore, a combination therapy of gossypol and autophagy inhibitors may lead to an enhanced anti−HCC effect.