cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells.
cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells.
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DOI：
10.1089/biores.2012.0270
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发表时间：
2012-12
影响因子：
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通讯作者：
Naviglio S
中科院分区：
文献类型：
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作者：
Spina A;Di Maiolo F;Esposito A;Sapio L;Chiosi E;Sorvillo L;Naviglio S
乳腺癌是最常见的恶性肿瘤之一，也是全世界妇女癌症死亡的主要原因。与乳腺癌相关的高死亡率主要是由于肿瘤转移的倾向，即使很小或无法检测。鉴于瘦素在乳腺癌生长和转移中的相关作用，有必要采取新的策略来抵消这种肥胖相关细胞因子的生物学效应。最近，我们证明了在MDA-MB-231乳腺癌细胞中，细胞内cAMP升高完全消除了ERK 1/2和STAT 3磷酸化对瘦素的反应。非常令人惊讶的是，这提供了证据，当cAMP水平增加时，瘦素驱动细胞凋亡，与Bcl 2蛋白水平的显著降低相关，并伴随着蛋白激酶A（PKA）的下调。本研究的目的是探讨cAMP在乳腺癌细胞瘦素相关运动中的作用。在这里，我们表明，cAMP升高完全阻止瘦素诱导的MDA-MB-231乳腺癌细胞的迁移。有趣的是，cAMP升高剂对瘦素介导的细胞迁移的抑制伴随着β3整联蛋白亚基和粘着斑激酶（FAK）蛋白水平的强烈降低。潜在的cAMP依赖的分子机制的分析表明，PKA阻滞剂部分抵消抑制瘦素诱导的迁移和完全阻止cAMP升高的抗增殖作用。此外，特异性激活Epac而非PKA的cAMP类似物也对瘦素诱导的细胞迁移具有抑制作用。本研究证实了cAMP升高对抗瘦素致癌效应的初步证据，鉴定了β3整合素亚基和FAK是cAMP升高强烈下调的蛋白质，并表明cAMP/PKA和cAMP/Epac依赖性途径均参与抑制瘦素诱导的MDA-MB-231乳腺癌细胞迁移。我们的数据的潜在临床意义和治疗应用进行了讨论。
Breast cancer is one of the most common malignancies and a major cause of cancer death among women worldwide. 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. Very surprisingly, this provided evidence that when cAMP levels are increased, leptin drives cells towards apoptosis associated with a marked decrease of Bcl2 protein levels and accompanied by down-regulation of protein kinase A (PKA). The aim of the current 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 partly counteract the inhibition of leptin-induced migration and completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue that specifically activates Epac and not PKA has an 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 of our data are discussed.