Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4-NQO-induced carcinogenesis.

High glutathione (GSH) levels are commonly found in oral tumors and are thought to play an important role in tumorigenesis. While posttranslational binding of GSH to cellular proteins (protein glutathiolation) has recently been recognized as an important redox-sensitive regulatory mechanism, no data currently exist on this process during carcinogenesis. Our goal was to determine the effects of 4-nitroquinoline-N-oxide (4-NQO)-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat. Male F-344 rats (6 weeks of age) were administered either 4-NQO (20 ppm) in drinking water or tap water alone (controls) for 8 weeks. Twenty-four weeks after cessation of 4-NQO, squamous cell carcinomas of the tongue were observed in all rats. The levels of both free and bound GSH in tumors, as well as in adjacent tissues, were 2- to 3-fold greater than in tongue epithelium from control rats (p < 0.05). Prior to tumor formation, at 8 weeks after cessation of 4-NQO, hyperplasia, dysplasia and carcinoma in situ were observed in 100%, 25% and 12.5% of 4-NQO-treated rats, respectively. At this early stage of carcinogenesis, levels of free and bound GSH were increased 50% compared with tongue tissues from control rats (p<0.05). Glutathione disulfide (GSSG) levels were also 2-fold greater in tongue tissues from 4-NQO treated vs. control rats (p<0.05). Altogether, these results suggest that protein glutathiolation, together with GSH and GSSG levels, are induced during oral carcinogenesis in the rat possibly as a result of enhanced levels of oxidative stress.

Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review).

Leptin is a hormone with multiple biological actions which is produced predominantly by adipose tissue; in humans, plasma levels correlate with total body fat, and particularly high concentrations occur in obese women. Several actions of leptin, including the stimulation of normal and tumor cell growth, migration and invasion, and enhancement of angiogenesis, suggest that this hormone can promote an aggressive breast cancer phenotype which can be estrogen-independent. This effect may involve activation of the transcription factor NFkappaB. Leptin can also induce aromatase activity, with the potential for the promotion of estrogen production from androstenedione in adipose tissue, and hence the stimulation of estrogen-dependent breast cancer progression. On this basis, we hypothesize that leptin, perhaps in association with insulin, the plasma concentrations of which correlate with those of leptin, has an important role in the known adverse effect of obesity on breast cancer.