Going malignant: the hypoxia‐cancer connection in the prostate

Abstract

The 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+ characteristic 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.

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

“…North et al (2005) have suggested that p53 may be involved in the angiogenic switch in some tumours. Altered growth characteristics in cell lines subjected to selection pressure has frequently been reported, but the underlying cause has rarely been identified, and generally the selected lines grow more slowly (Louie et al, 1992;Gibelli et al, 1996;Hochachka et al, 2002). We hypothesize that a mutational event is responsible for both increased susceptibility to apoptosis and the altered doubling time, consistent with the previous demonstration that the hypoxic environment facilitates mutational events (Graeber et al, 1996) and plausible especially in a cell line deficient in DNA mismatch repair.…”

Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model

“…4,14 High level of FASN has also been linked with poor prognosis and reduced disease-free survival in prostate cancer patients. 15,16 It has been reported that overexpression of FASN induces transformation of immortalized prostate epithelial cells into invasive adenocarcinomas, and transgenic mice expressing FASN in the prostate develop intraepithelial neoplasia, suggesting that FASN has an important role in the development and progression of prostate cancer.…”

BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF

“…These hypoxic regions often correlate with poor prognosis due to the ability of cells within these regions to become resistant to chemotherapeutic agents and radiation therapy (Caro, 2001;Knowles and Harris, 2001;Harris, 2002;Hochachka et al, 2002). By understanding the regulation of hypoxia-induced cell death, effective treatments against cancerous tumors can be developed.…”