Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells

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...

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Main Authors:	Wong, V KW, Li, T, Law, B YK, Ma, E DL, Yip, N C, Michelangeli, F, Law, C KM, Zhang, M M, Lam, K YC, Chan, P L, Liu, L
Format:	Online
Language:	English
Published:	Nature Publishing Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730398/

id	pubmed-3730398
recordtype	oai_dc
spelling	pubmed-37303982013-08-01 Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells Wong, V KW Li, T Law, B YK Ma, E DL Yip, N C Michelangeli, F Law, C KM Zhang, M M Lam, K YC Chan, P L Liu, L Original Article 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 Ca2+ ATPase pump, leading to autophagy induction through the activation of the Ca2+/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. Nature Publishing Group 2013-07 2013-07-11 /pmc/articles/PMC3730398/ /pubmed/23846222 http://dx.doi.org/10.1038/cddis.2013.217 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Wong, V KW Li, T Law, B YK Ma, E DL Yip, N C Michelangeli, F Law, C KM Zhang, M M Lam, K YC Chan, P L Liu, L
spellingShingle	Wong, V KW Li, T Law, B YK Ma, E DL Yip, N C Michelangeli, F Law, C KM Zhang, M M Lam, K YC Chan, P L Liu, L Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
author_facet	Wong, V KW Li, T Law, B YK Ma, E DL Yip, N C Michelangeli, F Law, C KM Zhang, M M Lam, K YC Chan, P L Liu, L
author_sort	Wong, V KW
title	Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
title_short	Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
title_full	Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
title_fullStr	Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
title_full_unstemmed	Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells
title_sort	saikosaponin-d, a novel serca inhibitor, induces autophagic cell death in apoptosis-defective cells
description	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 Ca2+ ATPase pump, leading to autophagy induction through the activation of the Ca2+/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.
publisher	Nature Publishing Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730398/
_version_	1611999804344238080

Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells

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