Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway ROLE OF PALMITIC ACID
Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway ROLE OF PALMITIC ACID
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DOI：
10.1074/jbc.m114.593210
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发表时间：
2014-10-31
影响因子：
4.8
通讯作者：
Yu, Zhi-Ling
中科院分区：
文献类型：
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作者：
Kwan, Hiu Yee;Fu, Xiuqiong;Yu, Zhi-Ling
肿瘤发生涉及肿瘤细胞与邻近的正常细胞（例如脂肪细胞）之间的持续通讯。脂肪细胞的典型功能是储存甘油三酯并为其他组织释放脂肪酸。本研究旨在查明脂肪细胞是否促进黑色素瘤细胞生长并探讨其潜在机制。在这里，我们从小鼠腹股沟脂肪组织中分离出脂肪细胞，并与黑色素瘤细胞共培养。我们发现，与单一培养的黑色素瘤相比，共培养的黑色素瘤具有更高的脂质积累。此外，在与负载有荧光染料的脂肪细胞共培养的黑色素瘤中检测到荧光标记的脂肪酸BODIPY (R) FLC16信号，这表明脂肪细胞向黑色素瘤细胞提供脂肪酸。与单一培养的黑色素瘤细胞相比，共培养的黑色素瘤细胞具有更高的增殖和磷酸化 Akt（Ser-473 和 Thr-450）表达。 Akt 突变体在黑色素瘤细胞中的过度表达降低了共培养增强的增殖。脂质组学研究表明，共培养的黑色素瘤的棕榈酸水平升高。有趣的是，我们发现棕榈酸刺激黑色素瘤细胞增殖，改变细胞周期分布，并增加磷酸-Akt（Ser-473 和 Thr-450）和 PI3K 的表达，但不增加磷酸-PTEN（磷酸磷酸酶和张力蛋白同源物）的表达。更重要的是，棕榈酸刺激的增殖在 Akt 过表达的黑色素瘤细胞中进一步增强，并通过 LY294002 或内源 Akt 敲低或 Akt 突变体过表达而减少。我们还发现，与对照细胞相比，棕榈酸预处理的 B16F10 细胞在小鼠体内生长出明显更大的肿瘤。综上所述，我们认为脂肪细胞可能作为棕榈酸的外源来源，通过激活 Akt 促进黑色素瘤细胞生长。
Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY (R) FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.