Epidemiologic studies show that increased dietary intake or higher blood levels of one specific carotenoid, beta-cryptoxanthin (BCX), is strongly associated with a reduced risk of lung cancer. However, the biological activities and molecular targets by which BCX functions as a chemopreventive agent against lung cancer are poorly understood. Recent studies show that both nicotine and nicotinic acetylcholine receptors (nAChRs) play crucial roles in cancer cell survival, proliferation, migration, invasion and angiogenesis. In particular, alpha 7-nAChR is the main subunit mediating the effects of nicotine in lung carcinogenesis. Here we report that BCX suppresses cancer cell motility and angiogenesis by inhibiting the expression of alpha 7-nAChR and its mediated PI3K pathway in vitro. Similar to MG624, an alpha 7-nAChR-specific antagonist, BCX significantly inhibited migration and invasion of alpha 7-nAChR positive lung cancer cells and endothelial cells in both transwell and wound healing assays, but both MG624 and BCX were inactive in alpha 7-nAChR negative cells. Moreover, BCX and MG624 were synergized in suppressing cell migration due to the fact that BCX, but not MG624, is effective at suppressing alpha 7-nAChR at both mRNA expression and protein levels. Furthermore, the inhibition of cell migration by BCX was attenuated in PTEN-deficient U87MG cells or MCF-7 cells which express constitutively active PI3K. BCX also effectively inhibited nicotine and PNU282987, an alpha 7-nAChR-specific agonist-stimulated cell migration, endothelial cell tube formation and microvessel outgrowth in an aortic ring model. Immunocytochemistry analysis showed that BCX effectively suppressed actin reorganization, lamellipodia and stress fiber formation induced by overexpression of wild type PI3K downstream molecules Rac and Rho, while constitutively active Rac and Rho attenuated the inhibition of cell migration by BCX. Moreover, BCX suppressed activities of matrix metalloproteinase (MMP)-2 and MMP9, two downstream molecules of alpha 7-nAChR/PI3K. Conclusively, these data demonstrate that BCX can inhibit cancer cell motility and angiogenesis by suppressing alpha 7-nAChR expression and its downstream PI3K pathway. This could be one of the potential mechanisms for the chemopreventive effect of BCX against lung cancer (Supported by NIH R01CA104932).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1394. doi:10.1158/1538-7445.AM2011-1394