Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways

Abstract

Obesity is known to be an important risk factor for many types of cancer, such as breast, prostate, liver and endometrial cancer. Recently, epidemiological studies have indicated that obesity correlates with an increased risk of developing ovarian cancer, the most lethal gynecological cancer in developed countries. Leptin is predominantly produced by adipocytes and acts as a growth factor and serum leptin levels positively correlate with the amount of body fat. In this study, we investigated the effects of leptin on the growth of ovarian cancer cells and the underlying mechanism(s) of action. Our results showed that leptin stimulated the growth of the OVCAR-3 ovarian cancer cell line using MTT assay and trypan blue exclusion. Using western blot analysis, we found that leptin enhanced the expression of cyclin D1 and Mcl-1, which are important regulators of cell proliferation and the inhibition of apoptosis. To investigate the signaling pathways that mediate the effects of leptin, cells were treated with leptin plus specific inhibitors of JAK2, PI3K/Akt and MEK/ERK1/2 and analysis of the phosphorylation state of proteins was carried out by western blot assays. We showed that the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways were involved in the growth-stimulating effect of leptin on ovarian cancer cell growth and the specific inhibitors of PI3K/Akt and MEK/ERK1/2 revealed that these two pathways interacted with each other. Our data demonstrate that leptin upregulates the expression of cyclin D1 and Mcl-1 to stimulate cell growth by activating the PI3K/Akt and MEK/ERK1/2 pathways in ovarian cancer.

Heterogeneity of neuroblastoma cell lines in insulin‐like growth factor 1 receptor/Akt pathway‐mediated cell proliferative responses

“…(45) Expression and accumulation of cyclin D1 occur at multiple levels, including increased transcription, translation and protein stability, and are affected by growth factors, (46) or signal pathways including PI3K-Akt pathway. (47) Ectopic expression of cyclin D1 induces G2 ⁄ M arrest. (48) In response to PPP and MK2206, cyclin B1 accumulated in all three groups, but cyclin D1 was declined only in groups 1 and 2 NB cell lines, and not in group 3 (data not shown).…”

High Leptin Level is an Independent Risk Factor of Endometrial Cancer: A Meta-Analysis

“…But the findings from the meta-analysis shows that high leptin level is an independent risk factor of endometrial cancer independent of BMI, which indicates that leptin may be involved in the endometrial carcinogenesis by other pathways. Previous studies have suggested that leptin plays a major role in the regulation of glucose, insulin-sensitizing activity, inflammation, lipid homeostasis, and other pathophysiology involved in carcinogenesis [33,34,35]. Previous studies also have suggested that leptin can stimulate cell growth, invasion, and angiogenesis via activating different signaling pathways [9,36,37], which may promote the development of endometrial cancer.…”

Obesity and female malignancies

“…Over-expression of the membrane receptors for leptin has been observed in about 60% of ovarian cancers, and it correlates with poor progression-free survival [61]. Recent data demonstrate that leptin enhances cell growth by activating the Janus kinase 2 (JAK2), MEK/ERK1/2 and PI3K/Akt pathways in ovarian cancer [62]. Furthermore, leptin upregulates the expression of vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2), which play important roles in tumour angiogenesis [63].…”