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.
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.
Department of Veterinary Medicine, School of Veterinary Medicine,                     National Taiwan University, Taipei, Taiwan, R.O.C.
Chiachen
C
Chen
Yuan-Ching
YC
Chang
Michael S
MS
Lan
Mary
M
Breslin
D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D002070:Butadienes; D019938:Cyclin D1; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D053614:Janus Kinase 2; D020738:Leptin; D020929:Mitogen-Activated Protein Kinase Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020032:Tyrphostins; C113580:U 0126; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507924:JAK2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one