Estrogen receptor ß regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3.

ABSTRACT

Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN. INPP4B is up-regulated by androgens, and this suggests that androgen-deprivation therapy (ADT) would lead to hyperactivity of AKT. However, in the present study, we found that in PCa, samples from men treated with ADT, ERß, and INPP4B expression were maintained in some samples. To investigate the role of ERß1 in regulation of INPPB, we engineered the highly metastatic PCa cell line, PC3, to express ERß1. In these cells, INPP4B was induced by ERß ligands, and this induction was accompanied by inhibition of Akt activity and reduction in cell migration. These findings reveal that, in the absence of androgens, ERß1 induces INPP4B to dampen AKT signaling. Since the endogenous ERß ligand, 3ß-Adiol, is lost upon long-term ADT, to obtain the beneficial effects of ERß1 on AKT signaling, an ERß agonist should be added along with ADT.