Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic ac id (AHPN, CD437) induces apoptosis in a variety of cell types, many of whic h are cancer cells that resist the antiproliferative and/or differentiating effects of retinoids. While the retinoids exert their effects by binding t o the retinoic acid nuclear receptors (RARs) or retinoid X receptors (RXRs) , AHPN (CD437) binds to another protein with different ligand specificity. In nuclear extracts from HL-60R cells the binding of AHPN (CD437) was only minimally competed by either retinoic acid (tRA)or 9-cis-retinoic acid (9-c is-RA), the natural ligands for the RARs and RXRs, respectively. Moreover, AHPN (CD437) was unable to compete with either tRA or 9-cis-RA for binding to endogenous retinoid receptors in nuclear extracts from the MDA-MB-468 br east carcinoma cell line. Size exclusion chromatography revealed AHPN bindi ng to a 95 kDa protein(s) which is neither an RAR or RXR. Our results sugge st that apoptosis induction by AHPN (CD437) may occur through interaction w ith another protein and is independent of the RAR/RXR-signaling pathways. I nt. J. Cancer 86:474-479, 2000. (C) 2000 Wiley-Liss, Inc.