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

V. K.W. Wong, T. Li, B. Y.K. Law, Edmond Dik Lung MA, N. C. Yip, F. Michelangeli, C. K.M. Law, M. M. Zhang, K. Y.C. Lam, P. L. Chan, Liang LIU*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

109 Citations (Scopus)

Abstract

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 calciumlevel 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 mechanismof 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.

Original languageEnglish
Article numbere720
JournalCell Death and Disease
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 2013

Scopus Subject Areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

User-Defined Keywords

  • Apoptosis-resistant
  • Autophagic cell death
  • Autophagy
  • Saikosaponin-d
  • SERCA inhibitor

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