Mechanisms of Leptin Effects on Growth and Apoptosis of Endocrine-Related Cancer Cells
Date Issued
2007
Date
2007
Author(s)
Chen, Chia-chen
DOI
en-US
Abstract
Abstract
Leptin, one of the major hormones synthesized by adipocytes, is involved in the development of obesity associated cancers. It plays as a paracrine/ autocrine regulator mediating growth of various types of cancer cells. Effects of leptin in breast, ovarian and liver cancer cells were less studied, therefore in the present study, we used the three cancer cells to investigate leptin effects and its signaling pathways and mechanisms. In all three examined cancer cells, we found leptin induced cell proliferation and anti-apoptosis. Leptin-stimulated cell proliferation was achieved by provoking expression of cyclin D1 that speeds up cell-cycle progression. In breast and ovarian cancer calls, the expression of c-Myc, one of the transcription factors of cyclin D1 promoter, was enhanced by leptin. In addition, we observed leptin also down-regulated tumor suppressor p53 and cyclin-depedent kinase (CDK) inhibitor p21WAF1/CIP1 to promote cell-cycle progression. In both gynaecological cancer cells, leptin attenuated cell apoptosis by up-regulating expression of antiapoptotic MCL-1. In hepatocellular carcinoma (HCC) cells, the anti-apoptotic effects of leptin were mediated by decreasing expression of proapoptotic Bax. The results indicated the mechanism of leptin-inhibited anti-apoptosis is cell type-specific. In all three cancer cells, the intracellular signals of leptin were transduced by a Janus kinase 2 (JAK2)-linked pathways and at the downstream of JAK2, MEK1/2 and ERK1/2 are involved in the signaling cascade. Besides of JAK2, MEK1/2 and ERK1/2, in HCC cells, PI3K and Akt were participated in the leptin activated signaling pathway. We define that the signaling cascade of leptin in HCC is a JAK2-PI3K/Akt-MEK/ERK1/2. In breast cancer cells, not like in HCC, leptin has no influence on phosphorylation of Akt and leptin-induced signaling pathway is JAK2-PI3K-MEK/ERK1/2. Interestingly, in ovarian cancer cells, crosstalk between two signaling pathways, JAK2-MEK/ERK1/2 and PI3K/Akt, were activated by leptin. Our study demonstrated that in the three examined cancer cells, leptin promotes cell proliferation is generally mediated by stimulating the expression of cyclin D1 to accelerate cell-cycle progression. However the mechanism of leptin on inhibiting apoptosis is cell-specific. The signaling pathways activated by leptin are cell type-dependent.
Subjects
瘦體素
乳癌
肝腫瘤
卵巢癌
細胞生長
leptin
breast cancer
hepatocellular carcinoma
ovarian cancer
cell growth
SDGs
Type
thesis
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