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The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.

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Apelin and chemerin are adipocytokines that play important roles in many physiological and pathological processes throughout the body. Our previous study demonstrated that these two adipokines are expressed and secreted by epithelial and granulosa cancer cell lines. 17β-estradiol (E2) and insulin-like growth factor-1 (IGF-1) are important regulators of ovarian functions, and their roles are well known. This study investigated whether apelin and chemerin regulate proliferation and apoptosis of epithelial (OVCAR-3) and granulosa (COV434) ovarian cancer cell lines by interacting with E2 and IGF-1. Apelin and chemerin did not affect caspase-3 activation in either cell line. However, apelin abrogated the stimulatory effects of E2 on proliferation of OVCAR-3 cells and of IGF-1 on proliferation of COV434 cells independently of ERK1/2 and PI3K via crosstalk of apelin receptor with estrogen receptor alpha and IGF-1 receptor, respectively.

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Accumulating evidence suggests that leptin is expressed at higher levels in obese women and stimulates cell migration in epithelial cancers. However, the biology of ovarian cancer is different from others, mainly due to the production of estrogens because of the involvement of ovarian tissue, which is the main source of estrogens; as a result, the levels are at least 100- to 1000-fold higher than normal circulating levels. Thus, ovarian cancer tissues are exposed to 17β-estradiol, which promotes ovarian cancer cell migration and may modulate the effect of other hormones. Therefore, this study investigated the effects of 17β-estradiol (1 nmol/L) with leptin (1-40 ng/mL) at physiological levels, on the migration of OVCAR-3 and SKOV-3 ovarian cancer cells, and the expression levels and activity of metalloproteinases (MMPs) 2 and 9. Here, we found that leptin stimulated ovarian cancer cell line migration, which is mediated via the expression and activity of MMP-9 in the OVCAR-3 but not in the SKOV-3 cells. After the administration of 17β-estradiol and leptin, we observed antagonistic effects of 17β-estradiol on leptin-induced OVCAR-3 cell migration and MMP-9 expression and activity. Moreover, the antagonistic effect of 17β-estradiol on leptin-induced cancer cell migration was reversed by pretreatment of the cells with the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor. Taken together, our results, for the first time, show that in ovarian cancer cells ObR/ER, 17β-estradiol has an antagonistic effect on leptin-induced cell migration as well as MMP-9 expression and activity, which is mediated by the PI3K pathway.

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