Previously, we have shown that leptin potentiates the antiproliferative action of cAMP elevating agents in breast cancer cells and that the protein kinase A (PKA) inhibitor KT-5720 prevented the antiproliferative effects induced by the leptin plus cAMP elevation. The present experiments were designed to gain a better understanding about the PKA role in the antitumor interaction between leptin and cAMP elevating agents and on the underlying signaling pathways. Here we show that exposure of MDA-MB-231 breast cancer cells to leptin resulted in a strong phosphorylation of both ERK1/2 and STAT3. Interestingly, intracellular cAMP elevation upon forskolin pretreatment completely abrogated both ERK1/2 and STAT3 phosphorylation in response to leptin and was accompanied by a consistent CREB phosphorylation. Notably, leptin plus forskolin cotreatments resulted in a strong decrease of both PKA regulatory RIα and catalytic subunits protein levels. Importantly, pretreatment with the PKA inhibitor KT-5720 blocked the forskolin-induced CREB phosphorylation and prevented both the inhibition by forskolin of leptin-induced ERK1/2 and STAT3 phosphorylation and the PKA subunits down-regulation induced by the combination of leptin and forskolin. Altogether, our results indicate that leptin-dependent signaling pathways are influenced by cAMP elevation and identify PKA as relevantly involved in the pharmacological antitumor interaction between leptin and cAMP elevating drugs in MDA-MB-231 cells. We propose a molecular model by which PKA confers its effects. Potential therapeutic applications by our data will be discussed.
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|Titolo:||Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down-regulation in breast cancer cells.|
|Citazione:||Naviglio, S., DI GESTO, D., Illiano, F., Chiosi, E., Giordano, A., Illiano, G., et al. (2010). Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down-regulation in breast cancer cells. JOURNAL OF CELLULAR PHYSIOLOGY, 225(3), 801-809.|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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