13-acetoxysarcocrassolide exhibits cytotoxic activity against oral cancer cells through the interruption of the keap1/Nrf2/p62/SQSTM1 pathway: The need to move beyond classical concepts

Yi Chang Liu, Bo Rong Peng, Kai Cheng Hsu, Mohamed El-Shazly, Shou Ping Shih, Tony Eight Lin, Fu Wen Kuo, Yi Cheng Chou, Hung Yu Lin, Mei Chin Lu

Research output: Contribution to journalArticle

Abstract

13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.

Original languageEnglish
Article number382
JournalMarine Drugs
Volume18
Issue number8
DOIs
Publication statusPublished - Jul 2020

Keywords

  • 13-Acetoxysarcocrassolide
  • Apoptosis
  • Keap1/Nrf2/p62/SQSTM1
  • Oral cancer
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Drug Discovery

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