A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway.
A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway.
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DOI：
10.1186/s13045-016-0302-1
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发表时间：
2016-08-31
影响因子：
28.5
通讯作者：
Zuo Q
中科院分区：
文献类型：
--
作者：
Liu J;Pan C;Guo L;Wu M;Guo J;Peng S;Wu Q;Zuo Q
曲妥珠单抗是一种靶向HER 2的人源化抗体，对HER 2阳性胃癌表现出显著的治疗效果。然而，复发性治疗耐药性提出了革命性的要求。瓦尔堡效应和AKT信号通路参与了对曲妥珠单抗的耐药。我们前期的研究表明，MACC 1基因的过表达预示着胃癌的预后不良，并促进肿瘤细胞的增殖和侵袭。在这项研究中，我们发现MACC 1在曲妥珠单抗耐药细胞系中显著上调。此外，MACC 1的下调逆转了这种抗性。使用已建立的曲妥珠单抗耐药GC细胞系，在体外研究曲妥珠单抗和糖酵解抑制剂组合对细胞活力、细胞凋亡和细胞代谢的影响。我们评估了曲妥珠单抗联合草酸酯对HER 2阳性GC细胞系的已建立异种移植模型中肿瘤生长和代谢的影响。在这里，我们发现MACC 1在曲妥珠单抗耐药细胞系中显著上调。此外，MACC 1在曲妥珠单抗耐药细胞中的下调逆转了这种耐药性。过表达MACC 1诱导曲妥珠单抗耐药，增强瓦尔堡效应，激活PI 3 K/AKT信号通路，而下调MACC 1则表现出相反的作用。此外，当PI 3 K/AKT信号通路被抑制时，MACC 1对抗性和糖酵解的影响减弱。我们的研究结果表明MACC 1主要通过PI 3 K/AKT信号通路促进瓦尔堡效应，进一步增强胃癌细胞对曲妥珠单抗的耐药性。我们的研究结果表明，HER 2和瓦尔堡效应的共同靶向逆转曲妥珠单抗耐药在体外和体内，这表明该组合可能克服曲妥珠单抗耐药MACC 1过表达，HER 2阳性GC患者。本文的在线版本（doi：10.1186/s13045-016-0302-1）包含补充材料，可供授权用户使用。
Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent therapeutic resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. In this study, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 reversed this resistance. The effect of trastuzumab and glycolysis inhibitor combination on cell viability, apoptosis, and cell metabolism was investigated in vitro using established trastuzumab-resistant GC cell lines. We assessed the impact of trastuzumab combined with oxamate on tumor growth and metabolism in an established xenograft model of HER2-positive GC cell lines. Here, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 in trastuzumab-resistant cells reversed this resistance. Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effects of MACC1 on resistance and glycolysis were diminished. Our findings indicated that MACC1 promoted the Warburg effect mainly through the PI3K/AKT signaling pathway, which further enhanced GC cells trastuzumab resistance. Our results indicate that co-targeting of HER2 and the Warburg effect reversed trastuzumab resistance in vitro and in vivo, suggesting that the combination might overcome trastuzumab resistance in MACC1-overexpressed, HER2-positive GC patients. The online version of this article (doi:10.1186/s13045-016-0302-1) contains supplementary material, which is available to authorized users.
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