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首页> 外文期刊>BioResearch open access. >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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cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

机译：cAMP升高下调β3整合素和局灶性粘附激酶并抑制瘦素诱导的MDA-MB-231乳腺癌细胞迁移。

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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.
机译：乳腺癌是最常见的恶性肿瘤之一，也是全世界女性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到。考虑到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与肥胖相关的细胞因子的生物学作用。最近，我们证明了在MDA-MB-231乳腺癌细胞中，细胞内cAMP升高完全消除了对瘦素的反应，导致ERK1 / 2和STAT3磷酸化。非常令人惊讶的是，这提供了证据，表明当cAMP水平升高时，瘦素会促使细胞趋向凋亡，而凋亡与Bcl2蛋白水平的显着降低有关，并伴随蛋白激酶A（PKA）的下调。本研究的目的是研究cAMP在瘦素相关的乳腺癌细胞运动中的作用。在这里，我们显示cAMP升高完全阻止了瘦素诱导的MDA-MB-231乳腺癌细胞迁移。有趣的是，cAMP升高剂对瘦素介导的细胞迁移的抑制作用伴随着β3整联蛋白亚基和粘着斑激酶（FAK）蛋白水平的强烈降低。对潜在的依赖cAMP的分子机制的分析表明，PKA阻滞剂部分抵消了对瘦素诱导的迁移的抑制作用，并通过cAMP升高完全阻止了抗增殖作用。而且，特异性激活Epac而不激活PKA的cAMP类似物也对瘦蛋白诱导的细胞迁移具有抑制作用。本研究证实了cAMP升高对瘦素致癌作用的有效性的初步证据，将β3整合素亚基和FAK识别为受cAMP升高强烈下调的蛋白质，并表明cAMP / PKA和cAMP / Epac依赖性途径均是参与抑制瘦素诱导的MDA-MB-231乳腺癌细胞迁移。讨论了我们数据的潜在临床意义和治疗应用。

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