Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor-1α in non-small cell lung cancer A549 cells.
Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor-1α in non-small cell lung cancer A549 cells.
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缺氧暴露在非小细胞肺癌A549细胞中通过激活p53和缺氧诱导因子1α的诱导诱导顺铂抗性。
DOI：
10.3892/ol.2018.8767
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发表时间：
2018-07
期刊：
影响因子：
2.9
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Guo Q;Lan F;Yan X;Xiao Z;Wu Y;Zhang Q
肺癌是全世界最常发生和致命的癌症类型之一。顺铂广泛用于非小细胞肺癌（NSCLC）的化疗。然而，顺铂的使用遇到了由于缺氧而导致的化学耐药性的挑战，缺氧在成人实体瘤中很常见，也是患者预后不良的主要原因。在本研究中，通过调节缺氧诱导因子 1α (HIF-1α) 和 p53 来评估缺氧对 NSCLC A549 细胞系对临床相关细胞毒性顺铂反应的影响。缺氧暴露上调了 A549 细胞中 HIF-1α 和 p53 的表达水平，并促进糖酵解，而通过引入 siRNA 敲低 HIF-1α 可减弱糖酵解，表明 HIF-1α 在缺氧条件下调节糖酵解中发挥着关键作用。 HIF-1α 敲低还使缺氧暴露的 A549 细胞对顺铂敏感，但在常氧暴露的 A549 细胞中则不然，这表明缺氧诱导的顺铂耐药在一定程度上导致了缺氧暴露导致的 HIF-1α 上调。本研究还确定缺氧上调的p53转录激活其下游靶基因p21并阻断细胞周期在G1-G0期，从而抑制细胞增殖。结果，激活的 p53 可能通过增加 A549 细胞的非增殖状态来使 A549 细胞对顺铂脱敏，从而最大限度地减少顺铂的影响。总而言之，这些结果确定了缺氧诱导的 HIF-1α 和 p53 的确切作用，并可能阐明它们对 A549 细胞对抗顺铂的保护作用。
Lung cancer is one of the most frequently occurring and fatal cancer types worldwide. Cisplatin is widely used for chemotherapy of non-small cell lung cancer (NSCLC). However, the use of cisplatin has been met with the challenge of chemoresistance as a result of hypoxia, which is common in adult solid tumors and is a principal cause of a poor patient outcome. In the present study, the effects of hypoxia on the response of the NSCLC A549 cell line to the clinically relevant cytotoxic cisplatin were evaluated via regulating hypoxia inducible facor-1α (HIF-1α) and p53. Hypoxia exposure upregulated the expression levels of HIF-1α and p53, and promoted glycolysis in A549 cells, which was attenuated by HIF-1α knockdown by siRNA introduction, indicating the critical roles of HIF-1α in regulating glycolysis under hypoxic conditions. HIF-1α-knockdown also sensitized A549 cells to cisplatin in hypoxia-exposed, but not in normoxia-exposed A549 cells, suggesting that hypoxia-induced cisplatin resistance partially contributes toward the upregulation of HIF-1α by hypoxia exposure. The present study also determined that hypoxia-upregulated p53 activated its downstream target gene p21 transcriptionally and blocked the cell cycle at the G1-G0 phase, thereby leading to inhibition of cell proliferation. As a result, activated p53 desensitized A549 cells to cisplatin potentially through increasing the non-proliferation status of A549 cells and therefore minimizing the influence of cisplatin. Taken together, these results identified the exact effects of HIF-1α and p53 induced by hypoxia and potentially elucidated their protective effects on A549 cells against cisplatin.
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