Regulation of LPA receptor function by estrogens

Abstract

17beta-Estradiol induced LPA(1) receptor desensitization in C9 cells stably expressing LPA(1) receptors and transiently expressing estrogen receptor alpha. Such desensitization was evidenced by a reduction in lysophosphatidic acid-mediated Ca(2+)mobilization and it was associated to receptor phosphorylation and internalization. These effects of 17beta-estradiol were rapid (taking place over 5 min) and were blocked by the estrogen receptor antagonist ICI 182780. Similarly, inhibitors of phosphoinositide 3-kinase (wortmannin and LY294002) and of protein kinase C (staurosporine and Gö 6976) blocked 17beta-estradiol-induced LPA(1) receptor desensitization and phosphorylation. Confocal microscopy evidenced LPA(1) receptor internalization in response to 17beta-estradiol treatment. Association between LPA(1) receptors and protein kinase C alpha was suggested by co-immunoprecipitation assays. Protein kinase C alpha was associated with LPA(1) receptors in the absence of stimulus and such association further increased in a dynamic fashion in response to 17beta-estradiol. The results demonstrated that in C9 cells estrogens modulate LPA(1) action through estrogen receptor alpha with the participation of protein kinase C alpha and phosphoinositide 3-kinase.

Lysophosphatidic acid receptor isoforms expression in prostate cancer cells is differentially regulated by the CYP17A1 inhibitor abiraterone and depends on the androgen receptor

“…Notably, in AR-positive LNCaP cells, we observed up-regulated (LPAR1, LPAR4, LPAR5), down-regulated (LPAR3, LPAR6) and unaltered (LPAR2) LPAR mRNA levels after 24 h of AA incubation. This was partially confirmed by Gonzáles-Arenas et al [12] . In breast cancer cells, the estrogen receptor agonist estradiol causes a declined expression of LPAR1, which could be reversed by incubation with the antagonist ICI 182780.…”

“…Therefore, AA-driven modulation of LPAR isoforms is more likely due to the control of LPAR expression than to the regulation of LPAR ligand synthesis by autotaxin catalysis. Studies of a breast cancer model confirmed this assumption, since LPAR expression has been shown to be linked to steroid hormone production and estrogen receptor activity [12,26] . The LPA receptors' mRNA expression pattern in PC cell lines PC-3 and LNCaP was shown for LPAR1-4.…”

“…LPA is a pivotal growth-stimulating factor in hormone-regulated tissues, e.g. mammary, endometrial, ovarian and prostatic tissues [10,12,16,21] . The secreted lipase autotaxin hydrolyzes lysophospholipids to LPA, which subsequently binds to its receptors LPAR1-LPAR6.…”

“…Two studies indicated that LPAR signaling in PC cells may depend on steroids. Bex et al demonstrated that G protein inhibition by the pertussis toxin is connected to PC cell growth attenuation, suggesting that this effect may be androgen-dependent [12][13][14] . The goal of the present study is to characterize AA's efficacy on LPAR expression.…”

Sharpening the edges of understanding the structure/function of the LPA1 receptor: Expression in cancer and mechanisms of regulation☆

“…This was further supported by the finding that both bradykinin and angiotensin-II stimulation promoted LPA1 phosphorylation. [82] In a recent follow-up to this work, studies showed that 17β-estradiol, acting through the estrogen receptor-α, leads to heterologous desensitization, phosphorylation, and internalization of LPA1 in both C9 cells and in ERα + T47D human breast cancer cells [83].…”