Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells.
Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells.
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磷脂酰肌醇3激酶/AKT/snail信号通路激活导致肝癌细胞上皮间质转化诱导索拉非尼多药耐药
DOI：
10.1371/journal.pone.0185088
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Dong J;Zhai B;Sun W;Hu F;Cheng H;Xu J
索拉非尼是一种口服激酶抑制剂，是晚期肝细胞癌（HCC）的标准一线全身用药，它通过抑制肝癌细胞中的丝裂原活化蛋白激酶（MAPK）信号通路，对上皮 - 间充质转化（EMT）和多药耐药（MDR）发挥强大的抑制活性。然而，长期接触索拉非尼后，肝癌细胞会出现EMT现象并对索拉非尼产生耐药性。索拉非尼对蛋白激酶B（AKT）的激活被认为是导致这些特性产生的原因。本研究旨在探究其潜在机制，并寻找逆转这种耐药性以及EMT进展的潜在策略。与亲代细胞相比，索拉非尼耐药细胞表现出更强的转移和侵袭能力，且P - 糖蛋白（P - gp）表达更高。这种现象至少部分归因于索拉非尼耐药肝癌细胞中出现的EMT和MDR。此外，MDR是EMT的下游分子事件。用小干扰RNA（siRNA）沉默Snail可阻断EMT并部分逆转MDR，从而显著消除索拉非尼耐药肝癌细胞的侵袭和转移能力，但沉默多药耐药基因1（MDR1）对EMT表型无影响。另外，稳定转染pCDNA3.1 - Snail的肝癌亲代细胞表现出EMT和MDR。从人肝癌HepG2和Huh7细胞建立的两种索拉非尼耐药肝癌细胞系对索拉非尼诱导的生长抑制具有抗性，但对新型变构AKT抑制剂MK - 2206敏感。因此，索拉非尼与MK - 2206联合使用可通过下调磷酸化的AKT，显著逆转EMT表型和P - gp介导的MDR。这些研究结果强调了EMT、MDR以及增强的磷脂酰肌醇 - 3激酶（PI3K）/AKT信号通路在索拉非尼耐药肝癌细胞中的重要意义。
Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial–mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.
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