""Breast cancer is one of the most common malignancies and a major cause of cancer death in women throughout the world. The high mortality rate associated with breast cancer is mainly due to a propensity of the tumor to metastasize, even if small or undetectable. Given the relevant role of leptin in breast cancer growth and metastasis, novel strategies to counteract biological effects of this obesity-linked cytokine are warranted.. Recently, we demonstrated that in MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1\\\/2 and STAT3 phosphorylation in response to leptin and, very surprisingly, provided evidence that leptin, when cAMP levels are increased, drives cells towards apoptosis associated to a marked decrease of Bcl2 protein levels and accompanied by down-regulation of Protein Kinase A (PKA).. The aim of this study was to investigate the role of cAMP in leptin-associated motility of breast cancer cells. Here we show that cAMP elevation completely prevents leptin-induced migration of MDA-MB-231 breast cancer cells. Interestingly, the inhibition by cAMP elevating agents of leptin-mediated cell migration is accompanied by a strong decrease of β3 integrin subunit and Focal Adhesion Kinase (FAK) protein levels. . Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers counteract in part the inhibition by cAMP elevation of leptin-induced migration, whereas completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue which specifically activates Epac and not PKA has inhibitory effect on leptin-induced cell migration as well.. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of leptin, identifies β3 integrin subunit and FAK as proteins strongly down-regulated by cAMP elevation and suggests that both cAMP\\\/PKA- and cAMP\\\/Epac-dependent pathways are involved in inhibition of leptin-induced migration of MDA-MB-231 breast cancer cells.. The potential clinical significance and therapeutic applications by our data will be discussed.. ""

cAMP elevation down-regulates beta3 integrin and Focal Adhesion Kinase and inhibits leptin-induced migration of MDA-MB-231 breast cancer cells

SPINA, Annamaria;SAPIO, Luigi;CHIOSI, Emilio;NAVIGLIO, Silvio
2012

Abstract

""Breast cancer is one of the most common malignancies and a major cause of cancer death in women throughout the world. The high mortality rate associated with breast cancer is mainly due to a propensity of the tumor to metastasize, even if small or undetectable. Given the relevant role of leptin in breast cancer growth and metastasis, novel strategies to counteract biological effects of this obesity-linked cytokine are warranted.. Recently, we demonstrated that in MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1\\\/2 and STAT3 phosphorylation in response to leptin and, very surprisingly, provided evidence that leptin, when cAMP levels are increased, drives cells towards apoptosis associated to a marked decrease of Bcl2 protein levels and accompanied by down-regulation of Protein Kinase A (PKA).. The aim of this study was to investigate the role of cAMP in leptin-associated motility of breast cancer cells. Here we show that cAMP elevation completely prevents leptin-induced migration of MDA-MB-231 breast cancer cells. Interestingly, the inhibition by cAMP elevating agents of leptin-mediated cell migration is accompanied by a strong decrease of β3 integrin subunit and Focal Adhesion Kinase (FAK) protein levels. . Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers counteract in part the inhibition by cAMP elevation of leptin-induced migration, whereas completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue which specifically activates Epac and not PKA has inhibitory effect on leptin-induced cell migration as well.. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of leptin, identifies β3 integrin subunit and FAK as proteins strongly down-regulated by cAMP elevation and suggests that both cAMP\\\/PKA- and cAMP\\\/Epac-dependent pathways are involved in inhibition of leptin-induced migration of MDA-MB-231 breast cancer cells.. The potential clinical significance and therapeutic applications by our data will be discussed.. ""
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11591/320843
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