Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism
Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism
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DOI：
10.1038/s41598-019-56675-6
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发表时间：
2019-12-27
影响因子：
4.6
通讯作者：
Wong, Vincent Kam Wai
中科院分区：
文献类型：
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作者：
Law, Betty Yuen Kwan;Michelangeli, Francesco;Wong, Vincent Kam Wai
癌细胞对化疗的抗性是一个重要的临床问题，并且在过去十年中已经广泛研究了癌症治疗中调节细胞死亡的机制，包括细胞凋亡、自噬或坏死。因此，高度期望通过新的作用机制鉴定针对化学抗性癌细胞的药用化合物。自噬在癌症治疗中诱导细胞死亡或存活中是重要的。最近，从天然产物中分离的新型自噬激活剂显示出以钙依赖性方式诱导抗凋亡癌细胞中的自噬细胞死亡。因此，增强自噬可以作为针对这些耐药癌症的额外治疗策略。通过计算对接分析，生化分析和先进的活细胞成像，我们确定甲基莲心碱，一种天然生物碱从莲，诱导自噬通过激活ryanodine受体和钙释放。使用众所周知的凋亡剂，如星形孢菌素、紫杉醇、多柔比星、顺铂和依托泊苷作为对照，甲基莲心碱显示通过钙动员通过激活兰尼碱受体和Ulk-1-PERK和AMPK-mTOR信号级联诱导一组癌细胞中的自噬性细胞死亡，所述癌细胞包括凋亡缺陷和抗性癌细胞或同基因癌细胞。总之，这项研究提供了深入了解甲基莲心诱导的自噬细胞毒性机制，通过兰尼碱受体激活耐药癌症。
Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and-resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.