Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis

Betty Y.K. Law, Mingfu Wang, Dik Lung Ma, Fawaz Al-Mousa, Francesco Michelangeli, Suk Hang Cheng, Margaret H.L. Ng, Ka Fai To, Anthony Y.F. Mok, Rebecca Y.Y. Ko, Sze Kui Lam, Feng Chen, Chi Ming Che, Pauline Chiu, Chi Bun Ko

Research output: Journal article publicationJournal articleAcademic researchpeer-review

114 Citations (Scopus)

Abstract

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound.
Original languageEnglish
Pages (from-to)718-730
Number of pages13
JournalMolecular Cancer Therapeutics
Volume9
Issue number3
DOIs
Publication statusPublished - 1 Mar 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this