Membrane-initiated estrogen signaling in prostate cancer: A route to epithelial-to-mesenchymal transition.

The plasma membrane (PM) is considered as a major druggable site. More than 50% of the existing drugs target PM proteins. In the wake of emerging data indicating a key role of estrogens in prostate cancer (PCa) pathogenesis, the study was undertaken to explore whether the estrogen binding sites exist on the PM and if such sites are functionally relevant in PCa. Estradiol (E2) binding to the PM was detected in androgen-dependent (LNCaP), androgen-independent (PC3, DU145) PCa cell lines, nontumorigenic (RWPE1) prostate epithelial cell line, and rat prostate cells. Conventional estrogen receptors (nuclear estrogen receptors), known for their nuclear localization, were detected in the PM enriched extracts. This was indirectly confirmed by reduced localization of ERs on the PM of cells, silenced for the expression of their cognate genes. Further, unlike cell-permeable E2, stimulation with cell-impermeable estradiol (E2-BSA) did not induce proliferation in LNCaP cells. However, stimulation with E2-BSA led to alterations in the phosphorylation status of several kinases including GSK3 and AKT, along with the hyperphosphorylation of cytoskeletal proteins such as ß-actin and cytokeratin 8 in LNCaP. This was accompanied by epithelial-to-mesenchymal (EMT) features such as increased migration and invasion; higher vimentin expression, and a concomitant decrease in the E-cadherin expression. These effects were not observed in RWPE1 cells. Interestingly, cell-permeable E2 failed to induce EMT in PCa cells. This in vitro study is the first to suggest that the PM-initiated estrogen signaling contributes to higher invasiveness in PCa cells. Plasma membrane ERs may act as novel targets for PCa therapeutics.

Estrogen matters in metastasis.

Metastatic cancer cells meet several physical, biochemical and immunological barriers before colonizing a new territory. Cancerous cells turn invasive, mobile and eventually disengage from their native niche. This is followed by their intravasation, extravasation, survival, proliferation, and colonization into distant organs. Unlike well-confined tumors, which respond favorably to anti-cancer therapeutics, metastatic tumors are life-threatening and incurable. More than 90% of cancer-related mortality is caused by metastases, hence the emphasis is now on developing the strategies to block or reverse the process of metastasis. This has ensued intensive research with a focus on the mechanisms underlying metastasis. Substantial work carried out in this direction has led to the identification of specific enzymes, proteins, cytokines, chemokines, growth factors, exosomes, miRNA and lipids, etc. as the facilitators of metastasis. Metastatic cells are exposed to a diverse array of local and systemic signals. Among these, estrogens are of great relevance. Estrogens have been strongly linked to cancers, especially of breast and uterine origin. Recent data hint that estrogens, well recognized for their role in proliferation, may have a role in metastasis also. It is proposed that influence of estrogen on metastasis may be independent of its proliferation-inducing ability. Data are emerging to suggest that estrogens have potential to modulate various events of the metastatic cascade such as local invasion, intravasation, anoikis, immune evasion, extravasation, angiogenesis and metastatic colonization. This review summarizes some of the recent advances in our knowledge on the role of estrogens in the metastatic cascade of cancerous cells.