Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells.
Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1beta); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1beta was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells.
Carino
Cecilia
C
Boston Biomedical Research Institute (BBRI), Watertown, MA, USA.
Olawaiye
Alexander B
AB
Cherfils
Salandre
S
Serikawa
Takehiro
T
Lynch
Maureen P
MP
Rueda
Bo R
BR
Gonzalez
Ruben R
RR
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism*; D015153:Blotting, Western; D016889:Endometrial Neoplasms / Q000098:blood supply / Q000378:metabolism*; D004717:Endometrium / Q000098:blood supply / Q000378:metabolism*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D053583:Interleukin-1beta; C507837:LIF protein, human; D020738:Leptin; D053605:Leukemia Inhibitory Factor; D017472:Receptors, Interleukin-1; D053606:Receptors, OSM-LIF; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases
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