Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways

D. Sharma, N. K. Saxena, P. M. Vertino, F. A. Anania

Research output: Contribution to journalArticlepeer-review

Abstract

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.

Original languageEnglish (US)
Pages (from-to)629-640
Number of pages12
JournalEndocrine-related cancer
Volume13
Issue number2
DOIs
StatePublished - Jun 2006
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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