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Am. J. Respir. Cell Mol. Biol., Volume 18, Number 3, March, 1998 323-333

Inhibition of Cell Proliferation and Induction of Apoptosis by the Retinoid AHPN in Human Lung Carcinoma Cells

Hiroshi Adachi, Gloria Preston, Beth Harvat, Marcia I. Dawson, and Anton M. Jetten

Laboratories of Pulmonary Pathobiology and Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Retinoid Program, SRI International, Menlo Park, California

In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-dependent manner. A dramatic reduction in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine (BrdU) incorporation and flow-cytometric analyses indicated that treatment of H460 cells with AHPN induces cell-cycle arrest at the G1 phase. We therefore investigated the effect of AHPN on several regulatory proteins of the G1 phase of the cell-cycle. The cell-cycle arrest induced by AHPN was accompanied by an inhibition of the hyperphosphorylation of the retinoblastoma (Rb) protein, an indication of G1 arrest. Furthermore, two cyclin-dependent kinases, cdk2 and cdk4, which are normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partly related to an increase in p21WAF1/Cip1 (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin-dependent kinase inhibitor p27Kip1. The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a post-transcriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines, different mechanisms appear to be involved. The specificity with which AHPN and other retinoids induce growth arrest and p21 expression indicates that the action of AHPN is not mediated by RAR or RXR receptors, but involves a novel signaling pathway.




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