Studies have suggested that retinoids prevent lung cancer by interacting with nuclear retinoid receptors. However, clinical trials with β-carotene increased lung cancer mortality. We recently showed that β-carotene stimulates the proliferation of small airway-derived adenocarcinoma by increasing cAMP signaling. Here, we have tested the hypothesis that β-carotene may stimulate squamous cell carcinoma cells via similar mechanisms. We determined the effects of β-carotene in cell lines from squamous cell carcinomas and large airway epithelia on proliferation by MTT assays in the presence and absence of inhibitors. Signaling via cAMP/PKA was measured by immunoassays and PKA activation assay. Phosphorylated ERK1/2 was determined by Western blotting. β-carotene significantly inhibited proliferation and phosphorylation of ERK1/2 by Gαs-mediated signaling involving adenylyl cyclase, cAMP, PKA and ERK1/2. These findings introduce a non-genomic inhibitory mechanism of β-carotene and emphasize the need for the development of marker-guided lung cancer prevention.

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