Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

Abstract

The cellular functions regulated by 17β-estradiol (E2) start after the hormone binds to its receptors (i.e., ERα and ERβ). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERα to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERβ localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERβ to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERβ or in HeLa cells transiently transfected with ERβ or ERα expression vectors. As for ERα, palmitoylation is necessary for ERβ localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERα, the E2 binding increases ERβ association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERβ-E2 complex to activate p38 impairing the receptor-dependent activation of downstream pro-apoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERβ, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone. © 2007 Society for Endocrinology.