Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition.
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.
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Satoshi
S
Kitazawa
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Satoru
S
Nishizawa
Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Hideyuki
H
Nakagawa
Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Masaaki
M
Funata
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Kazuho
K
Nishimura
Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
Tomoyoshi
T
Soga
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Takahito
http://orcid.org/0000-0002-9941-9041
T
Hara
D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002402:Cathepsin D / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002402:Cathepsin D; D025262:Vacuolar Proton-Translocating ATPases
Cathepsin D; V-ATPase; colorectal cancer; patient selection marker; vulnerability