Adiponectin pathway attenuates malignant mesothelioma cell growth.
Adiponectin pathway attenuates malignant mesothelioma cell growth.
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DOI：
10.1165/rcmb.2011-0068oc
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发表时间：
2012-12
影响因子：
6.4
通讯作者：
K. Niu;M. Asada;Tatsuma Okazaki;S. Yamanda;T. Ebihara;Hui Guo;Dongyin Zhang;R. Nagatomi;H. Arai;M. Kohzuki;S. Ebihara
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文献类型：
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作者：
K. Niu;M. Asada;Tatsuma Okazaki;S. Yamanda;T. Ebihara;Hui Guo;Dongyin Zhang;R. Nagatomi;H. Arai;M. Kohzuki;S. Ebihara
恶性间皮瘤(MM)是由接触石棉引起的。由于多发性骨髓瘤潜伏期长，生存时间短，对目前的治疗方案反应不佳，因此需要长期的预防策略来抑制石棉暴露后病理状态的进展。越来越多的证据表明，脂联素通过促进AMP激活的蛋白激酶(AMPK)的激活，在能量代谢的调节中起着至关重要的作用。一些研究表明，AMPK的激活降低了环氧合酶(COX)-2的表达。由于高水平的COX-2水平与MM的预后和生存率有关，我们研究了脂联素途径是否通过AMPK/COX-2途径抑制MM细胞的生长。在体内，鱼油(脂联素的潜在促进剂)降低了MM的生长速度，同时伴随着脂联素和磷酸化AMPK水平的增加，COX-2水平的下降。在体外，脂联素显著降低MM细胞的增殖率。这些作用部分涉及诱导多发性骨髓瘤细胞的生长停滞和凋亡。MM细胞表达脂联素受体1和2(AdipoR1和-R2)，在mRNA和蛋白水平均有表达。这些受体是有功能的，因为脂联素激活了AMPK。脂联素治疗还显著下调COX-2及其下游前列腺素E(2)的蛋白水平。最后，通过小干扰RNA敲除对AdipoR1/R2的抑制分析表明，脂联素主要通过AdipoR1增强AMPK活性，并损害MM细胞的增殖率。这些发现表明，诱导或补充脂联素是制定治疗MM策略的重要策略。
Malignant mesothelioma (MM) is caused by exposure to asbestos. Because MM has a latency period, short survival time, and has a poor response to current therapeutic regimes, long-term preventive strategies are required to suppress the advance of pathological states after asbestos exposure. Accumulating evidence suggests that adiponectin plays a crucial role in the regulation of energy metabolism by increasing AMP-activated protein kinase (AMPK) activation. Several studies have indicated that the activation of AMPK decreases cyclooxygenase (COX)-2 expression. Because high COX-2 levels correlated with a worse prognosis and survival rate in MM, we examined whether the adiponectin pathway suppresses MM cell growth through the AMPK/COX-2 pathway. In vivo, dietary fish oil (a potential promoter of adiponectin) decreased the growth rate of MM, which was accompanied by an increase in adiponectin and phospho-AMPK levels, and a decrease in COX-2 level. In vitro, adiponectin significantly impaired the cell proliferation rate of MM cell lines. These effects partly involved induction of growth arrest and apoptosis to MM cells. MM cells expressed both adiponectin receptors 1 and 2 (AdipoR1 and -R2) at mRNA and proteins levels. These receptors were functional, because adiponectin activated AMPK. Adiponectin treatment also significantly down-regulated protein levels of COX-2 and its downstream prostaglandin E(2). Finally, inhibitory analysis of AdipoR1/R2 by small interfering RNA knockdown suggests that adiponectin enhances AMPK activity and impairs the cell proliferation rate of MM cells, mainly via AdipoR1. These findings suggest that the induction or supplementation of adiponectin is an important tactic for developing therapeutic strategies against MM.