N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization
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 imp...
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doaj-b7ad2f93dbb546ee897ee16ceb94825e2020-11-24T23:11:56ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-06-01810.3389/fphar.2017.00388270042N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ MobilizationBetty Y. K. Law0Simon W. F. Mok1Juan Chen2Francesco Michelangeli3Zhi-Hong Jiang4Yu Han5Yuan Q. Qu6Alena C. L. Qiu7Su-Wei Xu8Wei-Wei Xue9Xiao-Jun Yao10Xiao-Jun Yao11Jia Y. Gao12Masood-ul-Hassan Javed13Paolo Coghi14Liang Liu15Vincent K. W. Wong16State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaThe Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical UniversityChongqing, ChinaDepartment of Biological Sciences, University of ChesterChester, United KingdomState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaCollege of Chemistry and Chemical Engineering, Lanzhou UniversityLanzhou, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaCollege of Chemistry and Chemical Engineering, Lanzhou UniversityLanzhou, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaCollege of Medicine, King Saud Bin Abdulaziz University for Health SciencesJeddah, Saudi ArabiaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyMacau, ChinaResistance 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 N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca2+/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.http://journal.frontiersin.org/article/10.3389/fphar.2017.00388/fullN-desmethyldauricineSERCAautophagyautophagic cell deathapoptosis-resistant |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Betty Y. K. Law Simon W. F. Mok Juan Chen Francesco Michelangeli Zhi-Hong Jiang Yu Han Yuan Q. Qu Alena C. L. Qiu Su-Wei Xu Wei-Wei Xue Xiao-Jun Yao Xiao-Jun Yao Jia Y. Gao Masood-ul-Hassan Javed Paolo Coghi Liang Liu Vincent K. W. Wong |
spellingShingle |
Betty Y. K. Law Simon W. F. Mok Juan Chen Francesco Michelangeli Zhi-Hong Jiang Yu Han Yuan Q. Qu Alena C. L. Qiu Su-Wei Xu Wei-Wei Xue Xiao-Jun Yao Xiao-Jun Yao Jia Y. Gao Masood-ul-Hassan Javed Paolo Coghi Liang Liu Vincent K. W. Wong N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization Frontiers in Pharmacology N-desmethyldauricine SERCA autophagy autophagic cell death apoptosis-resistant |
author_facet |
Betty Y. K. Law Simon W. F. Mok Juan Chen Francesco Michelangeli Zhi-Hong Jiang Yu Han Yuan Q. Qu Alena C. L. Qiu Su-Wei Xu Wei-Wei Xue Xiao-Jun Yao Xiao-Jun Yao Jia Y. Gao Masood-ul-Hassan Javed Paolo Coghi Liang Liu Vincent K. W. Wong |
author_sort |
Betty Y. K. Law |
title |
N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization |
title_short |
N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization |
title_full |
N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization |
title_fullStr |
N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization |
title_full_unstemmed |
N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization |
title_sort |
n-desmethyldauricine induces autophagic cell death in apoptosis-defective cells via ca2+ mobilization |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2017-06-01 |
description |
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 N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca2+/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. |
topic |
N-desmethyldauricine SERCA autophagy autophagic cell death apoptosis-resistant |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00388/full |
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