Alteration in the expression of the chemotherapy resistance‑related genes in response to chronic and acute hypoxia in pancreatic cancer.

Abstract

Pancreatic cancer is currently one of the least curable types of human cancer and remains a key health problem. One of the most important characteristics of pancreatic cancer is its ability to grow under hypoxic conditions. Hypoxia is associated with resistance of cancer cells to radiotherapy and chemotherapy. It is a major contributor to pancreatic cancer genetic instability, which local and systemic resistance that may result in poor clinical outcome. Accordingly, identifying gene expression changes in cancer resistance genes that occur under hypoxic conditions may identify a new therapeutic target. The aim of the present study was to explore the association between hypoxia and resistance to chemotherapy and determine the alteration in the expression of cancer resistance-related genes in the presence of hypoxia. Pancreatic cancer cells (PANC-1) were exposed to 8 h hypoxic episodes (<1% oxygen) three times/week for a total of 20 episodes (chronic hypoxia) or 72 h hypoxic episodes twice/week for a total of 10 episodes (acute hypoxia). The alterations in gene expression were examined using reverse transcription-quantitative PCR array compared with normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay. Both chronic and acute hypoxia induced chemoresistance toward doxorubicin in PANC-1 pancreatic cancer cell line. The greatest changes occurred in estrogen Receptor Alpha Gene (ESR1) and ETS Like-1 protein (ELK1) pathways, in nucleic transcription factor Peroxisome proliferator-activated receptors (PPARs) and in a cell cycle inhibitor cyclin dependent kinase inhibitor 1A (CDKN1A). The present study demonstrated that exposing cells to prolonged hypoxia results in different gene expression changes involving pleotropic pathways that serve a role in inducing resistance in pancreatic cancer.