Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma
Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma
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DOI：
10.1007/s13277-014-2633-2
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Ding, Gang
中科院分区：
文献类型：
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作者：
Hua, Hong-Wei;Jiang, Feng;Ding, Gang
分泌的蛋白质，酸性和富含半胱氨酸（半胱氨酸），钙结合基质细胞糖蛋白，涉及许多癌症的进展。目前，有越来越多的证据表明，在各种癌症中的重要功能，其在癌症中的作用取决于肿瘤类型。在这项研究中，我们报道了在肝细胞癌（HCC）中，葡萄糖代谢的负调控。过表达的pGEX通过下调葡萄糖代谢关键酶抑制葡萄糖摄取和乳酸生成。另一方面，敲低的β-淀粉样蛋白逆转了表型。同时，外源性表达的HepG 2细胞对低糖的耐受性与AMPK通路有关。有趣的是，5-氟尿嘧啶（5-FU）耐药的HepG 2细胞显示出葡萄糖代谢增加和下调β-内酰胺酶水平。最后，我们报道了在体外和体内通过抑制糖酵解来过度表达对5-FU敏感的5-FU耐药细胞。我们的研究提出了一个新的功能，在肝细胞癌的葡萄糖代谢的调节，并将促进肝癌患者的治疗策略的发展。
Secreted protein, acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progression of many cancers. Currently, there is growing evidence for important functions of SPARC in a variety of cancers and its role in cancer depends on tumor types. In this study, we reported SPARC negatively regulated glucose metabolism in hepatocellular carcinoma (HCC). Overexpression of SPARC inhibited glucose uptake and lactate product through downregulation of key enzymes of glucose metabolism. On the other hand, knock down of SPARC reversed the phenotypes. Meanwhile, exogenous expression of SPARC in HepG2 cells resulted in tolerance to low glucose and was correlated with AMPK pathway. Interestingly, the 5-fluorouracil (5-FU)-resistant HepG2 cells showed increased glucose metabolism and down-regulated SPARC levels. Finally, we reported the overexpression of SPARC re-sensitize 5-FU-resistant cells to 5-FU through inhibition of glycolysis both in vitro and in vivo. Our study proposed a novel function of SPARC in the regulation of glucose metabolism in hepatocellular carcinoma and will facilitate the development of therapeutic strategies for the treatments of liver tumor patients.