Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor-1α in non-small cell lung cancer A549 cells.

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.