Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1α expression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells.
Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1α expression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells.
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DOI：
10.3892/ol.2014.1963
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发表时间：
2014-05
期刊：
影响因子：
2.9
通讯作者：
Chen NW
中科院分区：
文献类型：
--
作者：
Zhang J;Guo H;Zhu JS;Yang YC;Chen WX;Chen NW
磷脂酰肌醇-3-激酶（PI 3 K）/Akt信号通路在细胞增殖、转化、凋亡、肿瘤生长和血管生成中起重要作用。紫杉醇通常用于治疗多种人类恶性肿瘤;然而，紫杉醇在胃癌（GC）中的潜在机制尚未得到充分研究。本研究收集45例胃癌和36例慢性胃炎患者的胃黏膜标本，采用免疫组织化学方法检测PI 3 K、磷酸化Akt（p-Akt）和缺氧诱导因子-1 α（HIF-1α）的表达，分析其与胃癌临床病理特征的关系。缺氧条件下的人SGC-7901 GC细胞用PI 3 K抑制剂LY 294002（40 μM）和紫杉醇（0.1 μM）预处理。采用定量聚合酶链反应（PCR）和Western blotting检测PI 3 K、p-Akt和HIF-1α的表达水平。细胞增殖活性和凋亡通过细胞计数试剂盒-8测定和流式细胞术来评估。胃癌组织中PI 3 K、p-Akt和HIF-1α的阳性表达率明显高于慢性胃炎组（P均<0.01），并与TNM分期、淋巴结转移、淋巴管浸润、血管浸润呈正相关胃癌组与肿瘤分化程度呈负相关（P <0.01）。在缺氧条件下，联合应用紫杉醇抑制PI 3 K/Akt信号通路可显著降低胃癌细胞的增殖活性，诱导胃癌细胞凋亡（P<0.01），并伴有HIF-1α表达的降低。PI 3 K/Akt/HIF-1α通路的表达与肿瘤分化程度、TNM分期、淋巴结转移、淋巴管和血管浸润密切相关。PI 3 K/Akt通路的抑制可增强紫杉醇对缺氧条件下胃癌细胞的治疗作用，提示PI 3 K/Akt/HIF-1α通路可能是紫杉醇治疗胃癌的重要靶点。
The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, transformation, apoptosis, tumor growth and angiogenesis. Paclitaxel is commonly used to treat multiple human malignancies; however, the underlying mechanisms of paclitaxel in gastric cancer (GC) have not been fully investigated. In the present study, specimens from 45 GC and 36 chronic gastritis patients were collected, and the correlations of PI3K, phosphorylated-Akt (p-Akt) and hypoxia-inducible factor-1α (HIF-1α) expression with the clinicopathological characteristics of GC were analyzed by immunohistochemistry. The human SGC-7901 GC cells under hypoxic conditions were pretreated with the PI3K inhibitor, LY294002 (40 μM), and paclitaxel (0.1 μM). The expression levels of PI3K, p-Akt and HIF-1α were detected by quantitative polymerase chain reaction and western blotting. Cell proliferative activity and apoptosis were evaluated by the Cell Counting Kit-8 assay and flow cytometry. As a result, the rates of positive expression of PI3K, p-Akt and HIF-1α were significantly higher in GC compared with chronic gastritis patients (each P<0.01), and were positively associated with the tumor-node-metastasis (TNM) staging, lymph node metastases, lymphatic infiltration and vascular infiltration (each P<0.01), but inversely correlated with tumor differentiation (P<0.01) in patients with GC. Under hypoxic conditions, the combined inhibition of the PI3K/Akt pathway with paclitaxel markedly reduced the proliferative activity and induced cell apoptosis in GC cells compared with the single treatment of PI3K inhibitor or paclitaxel (each P<0.01), and was accompanied by a decreased expression of HIF-1α. Overall, our findings indicate that the increased expression of the PI3K/Akt/HIF-1α pathway was closely correlated with tumor differentiation, TNM staging, lymph node metastases and lymphatic and vascular infiltration. The inhibition of the PI3K/Akt pathway enhanced the therapeutic efficacy of paclitaxel in GC cells under hypoxic conditions, suggesting that the PI3K/Akt/HIF-1α pathway may act as an important therapeutic target for paclitaxel treatment of GC.
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