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

The cellular functions regulated by 17 beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ER alpha and ER beta). 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 ERa 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 ER beta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ER beta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ER beta or in HeLa cells transiently transfected with ER beta or ERa expression vectors. As for ERa, palmitoylation is necessary for ER beta localization at the plasma membrane and its association with caveolin-11 but, in contrast to ER alpha, the E2 binding increases ER beta association with caveolin-11 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ER beta-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 ER beta, 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.