title: Overexpression of uncoupling protein-2 in cancer: metabolic and heat changes, inhibition and effects on drug resistance.
abstract: This paper deals with the role of uncoupling protein-2 (UCP2) in cancer. UCP2 is overexpressed in cancer. This overexpression results in uncoupling of mitochondrial oxidative phosphorylation and a shift in production of ATP from mitochondrial oxidative phosphorylation to cytosolic aerobic glycolysis. UCP2 overexpression results in the following changes. Mitochondrial membrane potential (Δψ(m)) is decreased and lactate accumulates. There is a diminished production of reactive oxygen species and apoptosis is inhibited post-exposure to chemotherapeutic agents. There is an increase in heat and entropy production and a departure from the stationary state of non-cancerous tissue. Uncoupling of oxidative phosphorylation may also be caused by protonophores and non-steroidal anti-inflammatory drugs. UCP2 requires activation by superoxide and lipid peroxidation derivatives. As vitamin E inhibits lipid peroxidation, it might be expected that vitamin E would act as a chemotherapeutic agent against cancer. A recent study has shown that vitamin E and another anti-oxidant accelerate cancer progression. UCP2 is inhibited by genipin, chromane compounds and short interfering RNAs (siRNA). Genipin, chromanes and siRNA are taken up by both cancer and non-cancerous cells. Targeting the uptake of these agents by cancer cells by the enhanced permeability and retention effect is considered. Inhibition of UCP2 enhances the action of several anti-cancer agents.
authors.affiliation: , P O Box 399, Paraparaumu, 5254, New Zealand. pitt@xtra.co.nz.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pitt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2; D014801:Vitamin A / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D014801:Vitamin A
keywords: Cancer; Non-steroidal anti-inflammatory drugs; Uncoupling protein-2 inhibition; Uncoupling protein-2 inhibition effect on chemotherapeutic agents; Uncoupling protein-2 overexpression; Vitamin E