Open AccessCancer with low cathepsin D levels is susceptible to vacuolar (H + )‐ATPase inhibition
Author(s) -
Kitazawa Satoshi,
Nishizawa Satoru,
Nakagawa Hideyuki,
Funata Masaaki,
Nishimura Kazuho,
Soga Tomoyoshi,
Hara Takahito
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13240
Subject(s) - cathepsin d , v atpase , downregulation and upregulation , cancer cell , cathepsin b , biology , intracellular , chemistry , microbiology and biotechnology , atpase , cancer research , cancer , biochemistry , enzyme , genetics , gene
Vacuolar (H + )‐ ATP ases (V‐ ATP ases) have important roles in the supply of nutrients to tumors by mediating autophagy and the endocytic uptake of extracellular fluids. Accordingly, V‐ ATP ases are attractive therapeutic targets for cancer. However, the clinical use of V‐ ATP ase inhibitors as anticancer drugs has not been realized, possibly owing to their high toxicity in humans. Inhibition of V‐ ATP ase may be an appropriate strategy in highly susceptible cancers. In this study, we explored markers of V‐ ATP ase inhibitor sensitivity. V‐ ATP ase inhibitors led to pH impairment in acidic intracellular compartments, suppression of macropinocytosis, and decreased intracellular amino acid levels. The sensitivity of cells to V‐ ATP ase inhibitors was correlated with low cathepsin D expression, and cancer cells showed increased sensitivity to V‐ ATP ase inhibitors after pretreatment with a cathepsin D inhibitor and si RNA targeting the cathepsin D gene ( CTSD ). In addition, V‐ ATP ase 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‐ ATP ase inhibitors are promising therapeutic options for cancers with downregulated cathepsin D.