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去甲基千金藤素通过钙动员在凋亡缺陷细胞中诱导自噬性细胞死亡。

-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca Mobilization.

作者信息

Law Betty Y K, Mok Simon W F, Chen Juan, Michelangeli Francesco, Jiang Zhi-Hong, Han Yu, Qu Yuan Q, Qiu Alena C L, Xu Su-Wei, Xue Wei-Wei, Yao Xiao-Jun, Gao Jia Y, Javed Masood-Ul-Hassan, Coghi Paolo, Liu Liang, Wong Vincent K W

机构信息

State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, China.

The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical UniversityChongqing, China.

出版信息

Front Pharmacol. 2017 Jun 16;8:388. doi: 10.3389/fphar.2017.00388. eCollection 2017.

DOI:10.3389/fphar.2017.00388
PMID:28670281
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5472688/
Abstract

Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified -desmethyldauricine (LP-4), isolated from as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca/Calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy.

摘要

癌细胞对化疗的耐药性仍然是肿瘤学中的一个重大问题。在过去几十年中，人们广泛研究了癌症治疗中调节程序性细胞死亡的机制，包括凋亡、自噬或坏死。自噬正逐渐成为癌症治疗中调节细胞死亡或存活的重要途径。最近的研究表明，多种天然小分子可在凋亡抗性癌细胞中诱导自噬性细胞死亡，因此，从天然产物中发现新型自噬增强剂可能是治疗化疗耐药癌症的一种有前景的策略。通过计算机虚拟对接分析、生化测定和先进的活细胞成像技术，我们从[具体植物名称]中分离出的去甲基千金藤碱（LP-4）鉴定为一种新型自噬诱导剂。LP-4通过Ulk-1-PERK和钙/钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）-AMPK-mTOR信号级联诱导自噬，通过抑制肌浆网钙ATP酶（SERCA）动员钙释放，重要的是，可导致一组癌细胞、凋亡缺陷和凋亡抗性细胞发生自噬性细胞死亡。综上所述，本研究详细深入地揭示了一种新型自噬化合物针对凋亡抗性癌细胞的细胞毒性机制，以及天然产物在耐药癌症治疗药物发现方面的新意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/35e3d568c1ef/fphar-08-00388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/78f1da3034f3/fphar-08-00388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/be217d410df0/fphar-08-00388-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/35b4b78726f9/fphar-08-00388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/bc85e27449bf/fphar-08-00388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/35e3d568c1ef/fphar-08-00388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/78f1da3034f3/fphar-08-00388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/be217d410df0/fphar-08-00388-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/1b5422bfedd6/fphar-08-00388-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/07a25eb18f85/fphar-08-00388-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/35b4b78726f9/fphar-08-00388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/bc85e27449bf/fphar-08-00388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc63/5472688/35e3d568c1ef/fphar-08-00388-g007.jpg

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