Smad3 Sensitizes Hepatocelluar Carcinoma Cells to Cisplatin by Repressing Phosphorylation of AKT.
Smad3 Sensitizes Hepatocelluar Carcinoma Cells to Cisplatin by Repressing Phosphorylation of AKT.
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Smad3 通过抑制 AKT 磷酸化使肝细胞癌细胞对顺铂敏感
DOI：
10.3390/ijms17040610
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发表时间：
2016-04-22
影响因子：
5.6
通讯作者：
Chen XP
中科院分区：
文献类型：
--
作者：
Zhou HH;Chen L;Liang HF;Li GZ;Zhang BX;Chen XP
背景：肝细胞癌（HCC）由于生物利用度有限和获得性耐药而对化疗不敏感。Smad 3在肝癌中具有抑制细胞生长和促进晚期肿瘤进展的双重作用。然而，smad 3在HCC化疗敏感性中的作用仍然是未知的。研究方法：通过细胞存活率、凋亡、平板集落形成试验和异种移植瘤模型检测smad 3在HCC化疗敏感性中的作用。通过蛋白质印迹法检测非smad信号传导，以寻找潜在的机制。结果：Smad 3能增强肝癌细胞对顺铂的敏感性。Smad 3在顺铂作用下上调p21 Waf 1/Cip 1，下调c-myc和bcl 2。此外，Smad 3的过表达抑制AKT的磷酸化，反之亦然。LY 294002抑制PI 3 K/AKT通路可恢复肝癌中smad 3缺陷细胞对顺铂的化疗敏感性。结论：Smad 3通过抑制AKT的磷酸化而使肝癌细胞对顺铂敏感，AKT通路抑制剂与常规化疗联合应用可能是解决肝癌耐药的潜在途径。
Background: Heptocelluar carcinoma (HCC) is insensitive to chemotherapy due to limited bioavailability and acquired drug resistance. Smad3 plays dual roles by inhibiting cell growth initially and promoting the progression of advanced tumors in HCC. However, the role of smad3 in chemosensitivity of HCC remains elusive. Methods: The role of smad3 in chemosensitivity of HCC was measured by cell viability, apoptosis, plate colony formation assays and xenograft tumor models. Non-smad signaling was detected by Western blotting to search for the underlying mechanisms. Results: Smad3 enhanced the chemosensitivity of HCC cells to cisplatin. Smad3 upregulated p21Waf1/Cip1 and downregulated c-myc and bcl2 with the treatment of cisplatin. Moreover, overexpression of smad3 repressed the phosphorylation of AKT, and vice versa. Inhibition of PI3K/AKT pathway by LY294002 restored chemosensitivity of smad3-deficiency cells to cisplatin in HCC. Conclusion: Smad3 sensitizes HCC cells to the effects of cisplatin by repressing phosphorylation of AKT and combination of inhibitor of AKT pathway and conventional chemotherapy may be a potential way to solve drug resistance in HCC.