Mannose 6-phosphate/insulin-like growth factor II receptor mediates the growth-inhibitory effects of retinoids

Both retinoids and the mannose 6-phosphate/insulin-like growth factor-ii re ceptor (M6P/IGF2R) have been shown to play an important role in controlling cell growth during embryonic development and oncogenesis. Our recent work (Kang ef al,, Proc. Natl, Acad, Sci, USA, 94: 13671-13676, 1997; Kang et al ,, Proc. Natl, Acad, Sci. USA, 95: 13687-13691, 1998) revealed a direct bio chemical interaction between retinoic acid (RA) and the M6P/IGF2R, thereby leading us to hypothesize that the M6P/IGF2R may mediate a growth-inhibitin g effect of RA, To test this hypothesis, cell growth and apoptosis in respo nse to RE and various receptor-selective retinoids were examined in cells t hat lack or overexpress the M6P/IGF2R, RA and those retinoids capable of bi nding to the M6P/IGF2R induced a remarkable morphological change with chara cteristics of round shape and reduced spreading, apoptosis, and growth inhi bition in stably transfected mouse P388D1 cells overexpressing the M6P/IGF2 R but not in the M6P/IGF2R-deficient P388D1 cells. These effects of RE were neither blocked by a potent RA nuclear receptor (RAR) antagonist (AGN19310 9), nor mimicked by a selective RAR agonist (TTNPB), suggesting that the ob served effects of RA are independent of RARs, Similar effects of the retino ids were observed in cultured neonatal rat cardiac myocytes that have high levels of the M6P/IGF2R. Furthermore, overexpression of the M6P/IGF2R in a RA-resistant cancer cell line (HL-GOR) that lacked functional RARs gave the cells a susceptibility to RA-induced apoptosis. These data suggest that th e M6P/IGF2R may play an important role in mediating retinoid-induced apopto sis/growth-inhibition and provide insight into the similar biological effec ts of RA and the M6P/IGF2R on fetal development and carcinogenesis.