EFFECTS OF PHYSIOLOGICAL VS. PHARMACOLOGICAL BETA-CAROTENE SUPPLEMENTATION ON P53 AND RARBETA EXPRESSION, AND JNK ACTIVATION IN THE LUNGS OF CIGARETTE SMOKE-EXPOSED FERRETS

Authors: LIU, CHUN - HNRCA; CHAVEZ, POLLYANNA - HNRCA; XU, XIAOCHUN - MD ANDERSON CANCER CTR; ORDOVAS, JOSE - HNRCA; LOTAN, ROBEN - MD ANDERSON CANCER CTR; RUSSELL, ROBERT - HNRCA; WANG, XIANG-DONG - HNRCA

Submitted to: Carotenoid Symposium
Publication Type: Abstract Only
Publication Acceptance Date: 10/15/2002
Publication Date: 6/1/2002
Citation: LIU, C., CHAVEZ, P., XU, X., ORDOVAS, J., LOTAN, R., RUSSELL, R.M., WANG, X. EFFECTS OF PHYSIOLOGICAL VS. PHARMACOLOGICAL BETA-CAROTENE SUPPLEMENTATION ON P53 AND RARBETA EXPRESSION, AND JNK ACTIVATION IN THE LUNGS OF CIGARETTE SMOKE-EXPOSED FERRETS. INTERNATIONAL CAROTENOID SYMPOSIUM. 2002;65.

Interpretive Summary:

Technical Abstract: Our previous study (Liu et al., Carcinogenesis, 2000) demonstrated that, in contrast to the pharmacological dose of beta-carotene, a physiological dose of beta-carotene in smoke-exposed ferrets afforded weak protection against smoke-induced lung cell proliferation and squamous metaplasia. In the present study, we further investigated the effects of these doses of beta-carotene on p53 and RARbeta tumor suppressor genes expression, and protein kinase signaling pathways. Ferrets were subjected to either a physiological (low) dose or a pharmacological (high) dose of beta-carotene supplementation (0.43 mg vs. 2.4 mg/kg body weight per day in the ferret; equivalent to 6 mg vs. 30 mg per day in humans) and cigarette smoke exposure for six months. Results show that there were greater levels of p53, phosphorylated Jun N-terminal kinase (JNK) and phosphorylated c-Jun protein, but not total JNK protein, in smoke-exposed ferrets with or without high dose beta-carotene supplementation and in ferrets given high dose beta-carotene supplementation alone. However, lung levels of phosphorylated-p38 protein and total-p38 protein were not altered by the treatments. No mutation was found by using direct sequencing 504-bp region of ferret lung p53 (equivalent to that of human p53 exons 5-8, which contains the major mutational hotspots in lung cancer) from any of the groups, indicating that p53 accumulation induced by smoke exposure may be due to its phosphorylation by JNK. In contrast, beta-carotene supplementation at low dose in smoke-exposed ferrets greatly attenuated the smoke-induced lung p53, phosphorylation of phosphorylated-JNK and c-Jun proteins. Interestingly, smoke exposure with and without high dose beta-carotene supplementation or high dose beta-carotene supplementation alone reduced pulmonary levels of RARbeta (assessed by both western blotting and nonisotopic in situ hybridization) and mitogen-activated kinase phosphatase-1 (MKP-1) protein, as compared with the lungs from control ferrets. In contrast, low dose beta-carotene supplementation (which acts as a precursor of retinoic acid when given at low levels) in smoke-exposed ferrets prevented the smoke-reduced pulmonary RARbeta and MKP-1. These data indicate that low dose beta-carotene may provide protection against smoking induced damage by blocking smoke-induced p53 accumulation, activation of JNK-dependent signaling pathway, and down-regulated RARbeta. (Supported by Grant #RSG-01-030-01-CNE from the American Cancer Society)