Vacuolar H(+)-ATPase: functional mechanisms and potential as a target for cancer chemotherapy.
Tumor cells in vivo often exist in a hypoxic microenvironment with a lower extracellular pH than that surrounding normal cells. Ability to upregulate proton extrusion may be important for tumor cell survival. Such microenvironmental factors may be involved in the development of resistant subpopulations of tumor cells. In solid tumors, both intracellular and extracellular pH differ between drug-sensitive and -resistant cells, and pH appears critical to the therapeutic effectiveness of anticancer agents. Four major types of pH regulators have been identified in tumor cells: the sodium-proton antiporter, the bicarbonate transporter, the proton-lactate symporter and proton pumps. Understanding mechanisms regulating tumor acidity opens up novel opportunities for cancer chemotherapy. In this minireview, we describe the structure and function of certain proton pumps overexpressed in many tumors--vacuolar H(+)-ATPases--and consider their potential as targets for cancer chemotherapy.
Torigoe
Takayuki
T
Department of Molecular Biology, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan.
Izumi
Hiroto
H
Ise
Tomoko
T
Murakami
Tadashi
T
Uramoto
Hidetaka
H
Ishiguchi
Hiroshi
H
Yoshida
Yoichiro
Y
Tanabe
Mizuho
M
Nomoto
Minoru
M
Kohno
Kimitoshi
K
D000970:Antineoplastic Agents / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006133:Growth Substances; D025262:Vacuolar Proton-Translocating ATPases