REGULATION OF APOPTOSIS BY THE RETINOID AHPN

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Retinoids are important regulators of development, cell growth and differentiation. Many of the effects of retinoids on gene expression are mediated through the nuclear retinoid receptors RARs and RXRs. However, the actions of certain retinoids such as retinoid 6-[3-(1- adamantyl)-4-hydroxy-phenyl]-2-naphthalene- carboxylic acid (AHPN) are not mediated by these nuclear receptors. AHPN inhibits the proliferation and induces apoptosis in many lung carcinoma and lymphoma cell lines. Flow cytometric analyses indicated that treatment of lung carcinoma H460 cells with AHPN induces G1 cell cycle arrest while it induces a G2 arrest in lymphoma cells. The induction of apoptosis is accompanied by an increase in annexin V binding and caspase-3-like activity. Overexpression of Bcl-2 inhibited the induction of apoptosis but did not block cell death. The caspase inhibitor ZVAD-fmk also inhibited cell death but did not affect the induction of growth arrest. The specificity by which AHPN and other retinoids induce growth arrest and apoptosis indicates that AHPN action is not mediated by RAR or RXR receptors but involves a novel signaling pathway. cDNA-macro array analysis identified a number of genes that are induced by AHPN. Many of these genes are involved in the control of cell growth and apoptosis. These include Egr-1, Nur77, GADD45, MyD118 and IRF-1. These genes are controlled by AHPN at both transcriptional and post-transcriptional mechanisms. Inhibition of MEK kinase but not of p38 MAPK blocks the induction of these genes by AHPN indicating that activation of the ERK MAPK signaling pathway is important in the induction of these genes by AHPN. - apoptosis, retinoids, growth control, lung carcinoma, retinoid receptors, lymphoma