Pterostilbene sensitizes cisplatin-resistant human bladder cancer cells with oncogenic HRAS

Yi Ting Chen, Zi Yi Huang, Han Hsuan Tang, Wan Ting Kuo, Shan Ying Wu, Sheng Hui Lan, Kai Hsun Chang, Pin Lun Lin, Ming Fen Lee, Hung Chi Cheng, Hsiao Sheng Liu, Chi Ying F. Huang, Guan Cheng Huang, Chun Li Su

Research output: Contribution to journalArticlepeer-review

Abstract

Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma. Further analysis revealed the roles of oncogenic HRAS, autophagy, and cell senescence signaling in bladder cancer cells sensitized to the anticancer drug cisplatin using the phytochemical pterostilbene. A T24 cell line with the oncogenic HRAS was chosen for further experiments. Indeed, coadministration of pterostilbene increased stronger cytotoxicity on T24 cells compared to HRAS wild-type E7 cells, which was paralleled by neither elevated apoptosis nor induced cell cycle arrest, but rather a marked elevation of autophagy and cell senescence in T24 cells. Pterostilbene-induced autophagy in T24 cells was paralleled by inhibition of class I PI3K/mTOR/p70S6K as well as activation of MEK/ERK (a RAS target) and class III PI3K pathways. Pterostilbene-induced cell senescence on T24 cells was paralleled by increased pan-RAS and decreased phospho-RB expression. Coadministration of PI3K class III inhibitor 3-methyladenine or MEK inhibitor U0126 suppressed pterostilbene-induced autophagy and reversed pterostilbene-enhanced cytotoxicity, but did not affect pterostilbene-elevated cell senescence in T24 cells. Animal study data confirmed that pterostilbene enhanced cytotoxicity of cisplatin plus gemcitabine. These results suggest a therapeutic application of pterostilbene in cisplatin-resistant bladder cancer with oncogenic HRAS.

Original languageEnglish
Article number2869
Pages (from-to)1-25
Number of pages25
JournalCancers
Volume12
Issue number10
DOIs
Publication statusPublished - 2020 Oct

Keywords

  • Autophagy
  • Cisplatin resistance
  • Gene database
  • HRAS
  • Pterostilbene
  • Senescence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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