Going malignant: the hypoxia‐cancer connection in the prostate

BioEssays - Tập 24 Số 8 - Trang 749-757 - 2002
Peter W. Hochachka1, Jim L. Rupert2, S. Larry Goldenberg3, Martin Gleave3, Piotr Kozłowski4,3
1Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
2Department of Pathology, University of British Columbia, Vancouver, BC, V6T 1Z4
3Vancouver General Hospital, Division of Urology, Vancouver, BC, V5Z 1M9
4Departments of Zoology and Radiology, University of British Columbia, Vancouver, BC, V6T 1Z4

Tóm tắt

AbstractThe metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ charactersitic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS‐facilitated redox improvement occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia‐regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the “low zinc, low citrate” phenotype reflects an hypoxia‐defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy. BioEssays 24:749–757, 2002. © 2002 Wiley Periodicals, Inc.

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BioEssays

Tập 24 Số 8

749-757

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