17-B estradiol elicits an autocrine leiomyoma cell proliferation: Evidence for a stimulation of protein kinase-dependent pathway

Abstract

The mechanism by which estradiol (E2) acts on cell proliferation is still unclear. In this paper, we report the results of a series of experiments in an attempt to elucidate the effector pathway(s) involved in coupling the E2 receptors binding to cellular growth response in leiomyoma cells (LSMC). Under conditions of E2-dependent growth, E2 treatment of LSMC triggers rapid and transient activation of the MAP-kinase pathway. Interestingly, we demonstrate that the early downstream signal transduction events determined by E2-stimulation in quiescent LSMC, including the rapid protein tyrosine phosphorylation of a subset of intracellular proteins, such GAP, PI-3-K, and PLCgamma, and the concomitant activation of ancillary protein kinases, are related to E2-induced PDGF secretion. Moreover, we identify the PDGF, alone or in association with other growth factors, as the main growth factor involved in the proliferation response of LSMC to E2 stimulation. The addition of neutralizing antibodies anti-PDGF was able to inhibit the mitogenic activity present in LSMC conditioned media samples. On the other hand, E2 did not affect the constitutive expression as well as the ligand affinity of PDGF receptors on LSMC plasmamembrane. Cell treatment with the antiestrogen ICI 182780 correlate both with a perturbation of E2-induced transductional circuit and with the disappearance of the mitogenic factor, PDGF, in LSMC conditioned media; the latter therefore, represents the main autocrine mediator of cell growth modulation, upregulated by E2 and down-regulated by antiestrogenic compound. Our experiments suggest that growth factor secretion is an initial and integral part of the signaling events mediated by the estradiol receptors, not related, at least in part, to E2 transcriptional modulation.

Expression profile of several genes in human myometrium and uterine leiomyoma

“…We chose to comment on PTN in this article because of its unique overexpression in our array, several reports that describe up-regulation of angiogenesis-related growth factors in leiomyoma (25,26), new advances in tumor biology, and the recognition that PTN is a growth factor that is elevated in tumor cells (27)(28)(29). Tumorigenesis is complex and is regulated in part by cellular phenotype growth, invasion, apoptosis, and angiogenesis.…”

Erythropoietin and erythropoietin receptor system in a large uterine myoma of a patient with myomatous erythrocytosis syndrome: possible relationship with the pathogenesis of unusual tumor size

“…Increasing evidence emphasize that this biologic mechanism is locally mediated by some growth factors [27][28][29][30][31] that, acting in an autocrine or paracrine manner, stimulate myoma growth mainly by mitogenic and angiogenic effects. A local deregulation of vasoactive growth factors or of their receptors has been hypothesized in the myomatous uterus [32].…”

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…For example, Barbarisi and colleagues demonstrated that E 2 treatment for 1, 5 and 30 min triggers rapid activation of phosphatidylinositide 3-kinases (PI3K), mitogen-activated protein kinase (MAPK) and phosphoinositide phospholipase Cγ (PLCγ) (32). In addition, Nierth-Simpson and colleagues (33) showed that E 2 treatment for 5 min activates protein kinase Cα (PKCα) in both human leiomyoma cells and human smooth muscle cells.…”