Loading...
Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca 2+ -dependent mechanism
Law, Betty Yuen Kwan Michelangeli, Francesco Qu, Yuan-Qing Xu, Su-Wei Han, Yu Mok, Simon Wing Fai De Seabra Rodrigues Dias, Ivo Ricardo Javed, Masood-Ul-Hassan Chan, Wai-Kit Xue, Wei-Wei
Law, Betty Yuen Kwan
Michelangeli, Francesco
Qu, Yuan-Qing
Xu, Su-Wei
Han, Yu
Mok, Simon Wing Fai
De Seabra Rodrigues Dias, Ivo Ricardo
Javed, Masood-Ul-Hassan
Chan, Wai-Kit
Xue, Wei-Wei
Advisors
Editors
Other Contributors
Affiliation
EPub Date
Publication Date
2019-12-27
Submitted Date
Collections
Files
Loading...
Article - VoR
Adobe PDF, 12.63 MB
Other Titles
Abstract
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.
Citation
Law, B. Y. K., Michelangeli, F., Qu, Y-Q., Xu, S-W., Han, Y., Mok, S. W. F., De Seabra Rodrigues Dias, I. R., Javed, M-U-H., Chan, W-K., Xue, W.-W., Yao, X-J., Zeng, W., Zhang, H., Wang, J-R., Liu, L., & Wong, V. K. W. (2019). Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca 2+ -dependent mechanism. Scientific Reports, 9(1), 20034. https://doi.org/10.1038/s41598-019-56675-6
Publisher
Nature Research
Journal
Scientific Reports
Research Unit
DOI
10.1038/s41598-019-56675-6
PubMed ID
PubMed Central ID
Type
Article
Language
Description
Series/Report no.
ISSN
EISSN
2045-2322