Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition

Satoshi Kitazawa, Satoru Nishizawa, Hideyuki Nakagawa, Masaaki Funata, Kazuho Nishimura, Tomoyoshi Soga, Takahito Hara

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Vacuolar (H+)-ATPases (V-ATPases) have important roles in the supply of nutrients to tumors by mediating autophagy and the endocytic uptake of extracellular fluids. Accordingly, V-ATPases are attractive therapeutic targets for cancer. However, the clinical use of V-ATPase inhibitors as anticancer drugs has not been realized, possibly owing to their high toxicity in humans. Inhibition of V-ATPase may be an appropriate strategy in highly susceptible cancers. In this study, we explored markers of V-ATPase inhibitor sensitivity. V-ATPase inhibitors led to pH impairment in acidic intracellular compartments, suppression of macropinocytosis, and decreased intracellular amino acid levels. The sensitivity of cells to V-ATPase inhibitors was correlated with low cathepsin D expression, and cancer cells showed increased sensitivity to V-ATPase inhibitors after pretreatment with a cathepsin D inhibitor and siRNA targeting the cathepsin D gene (CTSD). In addition, V-ATPase inhibitor treatment led to the induction of the amino acid starvation response, upregulation of endoplasmic reticulum stress markers, and suppression of mammalian target of rapamycin (mTOR) signaling in cells expressing low levels of cathepsin D. Some colorectal cancer patients showed the downregulation of cathepsin D in tumor tissues compared with matched normal tissues. These findings indicate that V-ATPase inhibitors are promising therapeutic options for cancers with downregulated cathepsin D.

Original languageEnglish
Pages (from-to)1185-1193
Number of pages9
JournalCancer science
Volume108
Issue number6
DOIs
Publication statusPublished - 2017 Jun

Keywords

  • Cathepsin D
  • V-ATPase
  • colorectal cancer
  • patient selection marker
  • vulnerability

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kitazawa, S., Nishizawa, S., Nakagawa, H., Funata, M., Nishimura, K., Soga, T., & Hara, T. (2017). Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition. Cancer science, 108(6), 1185-1193. https://doi.org/10.1111/cas.13240