Beta-cryptoxanthin reduced lung tumor multiplicity and inhibited lung cancer cell motility by downregulating nicotinic acetylcholine receptor alpha7 signaling

Authors: ISKANDAR, ANITA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MIAO, BENCHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LI, XINLI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HU, CONNIE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2016
Publication Date: 9/13/2016
Citation: Iskandar, A.R., Miao, B., Li, X., Hu, C., Liu, C., Wang, X. 2016. Beta-cryptoxanthin reduced lung tumor multiplicity and inhibited lung cancer cell motility by downregulating nicotinic acetylcholine receptor alpha7 signaling. Cancer Prevention Research. doi: 10.1158/1940-6207.CAPR-16-0161.

Interpretive Summary: Beta-cryptoxanthin (BCX,) abundant in red sweet peppers, tangerines, oranges, peaches, and pumpkins, is an oxygenated carotenoid (xanthophyll) with provitamin A activity. In the present study, the supplementation of BCX to the mice was effective in reducing the lung tumor number by 50% via reducing the alpha7-nicotine receptor. In the cell culture study, BCX reduced levels of alpha7-nicotine receptor expression and inhibited lung cancer cells' migration and invasion. The present study provided strong experimental evidence and described potential mechanisms to explain the significant protective association between a high intake of BCX and the risk of lung cancer among current smokers, reported previously in the analysis of seven prospective cohort studies and the Third Nutrition and Health Examination Survey database. The data supported that BCX can be used as a chemopreventive agent or a chemotherapeutic compound against lung cancer.

Technical Abstract: Despite the consistent association between a higher intake of the provitamin A carotenoid beta-cryptoxanthin (BCX) and a lower risk of lung cancer among smokers, potential mechanisms supporting BCX as a chemopreventive agent are needed. We first examined the effects of BCX on 4-[methyl nitrosamino]-1-[3-pyridyl]-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. BCX supplementation was given daily to the mice starting two-weeks prior to the injection of NNK and continued 16 weeks post NNK injection. BCX supplementation resulted in a dose-dependent increase of BCX concentration in both serum and lungs of the mice without a significant alteration of vitamin A (retinol and retinyl palmitate) concentration. BCX significantly reduced the multiplicity of the NNK-induced lung tumor by 52-63% compared to the NNK-treated mice without BCX supplementation. The protective effect of BCX in the lungs was associated with reductions of both mRNA and protein of the homopentameric neuronal nicotinic acetylcholine receptor alpha7 (alpha7-nAChR), which has been implicated in lung tumorigenesis. We then conducted an in vitro cell culture study, and found that BCX treatment suppressed alpha7-nAChR expression and inhibited the migration and invasion of alpha7-nAChR-positive lung cancer cells but not in cells lacking alpha7-nAChR. The activities of BCX were significantly attenuated by activators of alpha7-nAChR/PI3K signaling or by overexpression of constitutively active PI3K. Collectively, the results suggest that BCX inhibits lung tumorigenesis and cancer cell motility through the downregulation of alpha7-nAChR/PI3K signaling, independent of its provitamin A activity. Therefore, BCX can be used as a chemopreventive agent or a chemotherapeutic compound against lung cancer.