Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells
Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells
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DOI：
10.1111/j.1349-7006.2011.01902.x
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发表时间：
2011-05-01
期刊：
影响因子：
5.7
通讯作者：
Nagawa, Hirokazu
中科院分区：
文献类型：
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作者：
Habeeb, Baker S.;Kitayama, Joji;Nagawa, Hirokazu
已知脂联素对肿瘤生长具有抑制作用，并且被认为是肥胖和癌症之间正相关的关键分子。然而，调节肿瘤细胞活性的详细机制尚未阐明。在这项研究中，我们发现全长（f-Ad）和球状脂联素（g-Ad）在含葡萄糖的培养基中抑制结肠癌细胞系的细胞生长，而在葡萄糖剥夺培养基中支持细胞存活，增加AdipoR 1和AdipoR 2表达。脂联素在葡萄糖剥夺中的后一种作用通过加入自噬抑制剂、氯喹、3-甲基腺嘌呤或胃酶抑素A和E-64 d的组合而被显著抑制，这表明支持细胞生长的作用至少部分依赖于自噬的诱导。使用表达GFP-LC 3的稳定转染的DLD-1细胞，在荧光显微镜下，使用绿色荧光蛋白（GFP）-微管相关蛋白1轻链3（LC 3）融合蛋白，从形态学上确认自噬的增强。Western blot分析显示，脂联素可增加缺糖培养液中LC 3 -1、LC 3 -2、磷酸化AMPK α和PPAR α的表达，而降低磷酸化mTOR、胰岛素样生长因子（IGF）-1、磷酸化丝氨酸/苏氨酸激酶（Akt）和磷酸化磷脂酰肌醇3-激酶（PI 3 K）的表达。我们的结论是，脂联素通过AMPK α和PPAR α激活和IGF-1/PI 3 k/Akt/mTOR通路抑制增强自噬机制，支持葡萄糖剥夺中的细胞存活。脂联素的双峰效应被认为在肿瘤发生和进展的病理生理学中具有临床重要性。（Cancer Sci 2011; 102：999-1006）。
Adiponectin is known to have suppressive effects on tumor growth and is thought to be a key molecule in the positive correlation between obesity and cancer. However, the detailed mechanisms regulating tumor cell activity have not been elucidated. In this study, we found that both full-length (f-Ad) and globular adiponectin (g-Ad) inhibited cell growth in colon cancer cell lines in glucose-containing medium, whereas it supported cell survival in glucose-deprived medium, with an increase in AdipoR1 and AdipoR2 expression. The latter effect of adiponectin in glucose deprivation was significantly inhibited by adding autophagy inhibitors, chloroquine, 3-methyl adenine or a combination of pepstatin A and E-64d, suggesting that the effect of supporting cell growth was dependent, at least in part, on the induction of autophagy. The enhancement of autophagy was confirmed morphologically using green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) fusion proteins under a fluorescence microscope using stably transfected DLD-1 cells expressing GFP-LC3. Western blot analysis revealed that adiponectin increased the expression of LC3-1, LC3-2, phosphorylated AMPK alpha and PPAR alpha but decreased that of phosphorylated mTOR, insulin like growth factor (IGF)-1, phosphorylated serine/threonine kinase (Akt) and phosphorylated phosphatidylinositol 3-kinase (PI3K) in glucose-deprived medium. We conclude that adiponectin supports cell survival in glucose deprivation through enhancement of the autophagic machinery by AMPK alpha and PPAR alpha activation and IGF-1/PI3k/Akt/mTOR pathway inhibition. The bimodal effects of adiponectin are thought to be clinically important in the pathophysiology of tumor development and progression. (Cancer Sci 2011; 102: 999-1006).