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Saikosaponin-d, anovel SERCAinhibitor, inducesautophagic cell deathinapoptosis-defectivecells Vws WongTianpei LiBenedict Law2013 год

Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
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Аннотация: Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, leading to autophagy induction through the activation of the Ca(2+)/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.
Год издания: 2013
Авторы: Vws Wong, Tianpei Li, Benedict Law, Dik‐Lung Ma, Nga Chi Yip, Francesco Michelangeli, Calvin Law, M M Zhang, K YC Lam, Po Ling Chan, L Liu
Издательство: Springer Nature
Источник: Cell Death and Disease
Ключевые слова: Autophagy in Disease and Therapy, Endoplasmic Reticulum Stress and Disease, Sirtuins and Resveratrol in Medicine
Другие ссылки: Cell Death and Disease (PDF)
Cell Death and Disease (HTML)
PubMed Central (HTML)
PubMed (HTML)