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首页> 外文期刊>Journal of biosciences >Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4
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Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4

机译：通过反应性氧，P-糖蛋白和DKK4的葡萄糖依赖性改变促进了对多柔比蛋白和索拉非尼的肝细胞癌对多柔比星和索拉非尼的敏化进行促进

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Altered glucose uptake and metabolism is the key characteristic of cancer cells including hepatocellular carcinoma (HCC). However, role of glucose availability in chemotherapeutic outcome of HCC is unclear. The present study investigates the effect of glucose facilitated sensitization of HCC cells towards doxorubicin (DOX) and sorafenib (SORA). In HCC cells, we observed that hyperglycemic culture condition (HG) is associated with increased sensitivity towards DOX and SORA. P-glycoprotein (P-gp), a transporter involved in drug efflux, was elevated in HCC cells in NG, rendering them less susceptible to DOX and SORA. Further, this study demonstrated that knockdown of dickkopf protein 4 (DKK4), a Wnt antagonist protein, causes enhanced glucose uptake and reduction in P-gp level rendering HCC cells in NG sensitive to DOX and SORA. Moreover, HG elevates the level of intracellular reactive oxygen species (ROS), which regulates P-gp. Alteration in intracellular ROS did not directly affect regulation of DKK4 in HCC cells. Functional assays suggest that alterations in DKK4 and P-gp level in HCC cells are dependent on glucose availability and changes in ROS level because of enhanced glucose utilization, respectively. Collectively, the present study highlights direct involvement of glucose-induced ROS, DKK4 and P-gp in altering the sensitivity of HCC cells towards DOX and SORA.
机译：改变的葡萄糖摄取和新陈代谢是癌细胞的关键特征，包括肝细胞癌（HCC）。然而，葡萄糖可用性在HCC的化学治疗结果中的作用尚不清楚。本研究研究了葡萄糖促进HCC细胞对多柔比星（DOX）和Sorafenib（Sora）的敏化的影响。在HCC细胞中，我们观察到高血糖培养条件（HG）与对DOX和Sora的敏感性增加有关。 p-糖蛋白（p-gp），参与药物流出的转运蛋白在Ng中的HCC细胞中升高，使它们易受DOX和Sora的影响。此外，该研究表明，DickKopf蛋白4（DKK4），WNT拮抗剂蛋白质的敲低导致增强的葡萄糖摄取和降低对DOX和Sora的NG敏感性的HCC细胞。此外，HG升高了调节P-GP的细胞内反应性氧物质（ROS）的水平。细胞内RO的改变并没有直接影响HCC细胞中DKK4的调节。功能测定表明，HCC细胞中DKK4和P-GP水平的改变取决于葡萄糖可用性和ROS水平的变化，因为增强了葡萄糖利用率。集体，本研究突出了葡萄糖诱导的ROS，DKK4和P-GP在改变HCC细胞对DOX和Sora的敏感性方面的直接参与。

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