Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

Abstract

Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10−7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.

Mechanisms of action of nonpeptide hormones on resveratrol‐induced antiproliferation of cancer cells

“…Thyroid hormone stimulates the proliferation of ovarian cancer cells . Thyroid hormone (T 4 ) induces phosphorylation and nuclear augmentation of ERα . Both T 4 and E 2 induce nuclear translocation of integrin αv and phosphorylation of ERα .…”

“…Thyroid hormone (T 4 ) induces phosphorylation and nuclear augmentation of ERα . Both T 4 and E 2 induce nuclear translocation of integrin αv and phosphorylation of ERα . Blocking T 4 ‐induced ERK1/2 activation by ICI 182780, a specific ERα antagonist, inhibits the phosphorylation of ERα and nuclear colocalization of integrin αv and phosphorylated ERα.…”

“…Blocking T 4 ‐induced ERK1/2 activation by ICI 182780, a specific ERα antagonist, inhibits the phosphorylation of ERα and nuclear colocalization of integrin αv and phosphorylated ERα. The consequences are inhibition of expression of proliferative genes, such as proliferating cell nuclear antigen (PCNA), and eventually inhibition of proliferation . Thyroid hormone stimulates proliferation of ovarian cancer cells via cross talk between integrin αv and ERα, mimicking the functions of E 2 …”

“…The integrin α v β 3 antagonist RGD peptide has been used to block the binding site on integrin α v β 3 . Interestingly, RGD peptide can inhibit the binding sites of both thyroid hormone and resveratrol, and even the DHT binding site . The signal transduction pathways downstream of ERK1/2 activated by resveratrol versus thyroid hormone are distinct with regard to induction of antiproliferation by resveratrol and promotion of cancer cell proliferation by thyroid hormone .…”

“…On the other hand, estrogen acts as a promoter of breast cancer proliferation. Recent studies also indicate that thyroid hormone stimulates cell proliferation in various types of cancers, including glioma, breast cancer, and ovarian cancer . Steroid hormones have been shown to interfere with resveratrol‐induced antiproliferation .…”