Abstract
BackgroundMultidrug resistance (MDR) is one of the major reasons chemotherapy-based treatments fail. Hypoxia is generally associated with tumor chemoresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) gene/transporter P-glycoprotein (P-gp) remains unclear. This study aims to explore the molecular mechanisms of reversing colon cancer MDR by focusing on the target gene HIF-1α.MethodsA chemotherapeutic sensitivity assay was used to observe the efficiency of MDR reversal in LoVo multicellular spheroids (MCS). The apoptotic level induced by different drugs was examined by flow cytometry (FCM). Binding of HIF-1α to the MDR1 gene promoter was evaluated by Chromatin immunoprecipitation (ChIP). The relationship between HIF-1α/P-gp expression and sensitivity to chemotherapy was analyzed.ResultsThe sensitivity of LoVo MCS to all four chemotherapy drugs was decreased to varying degrees under hypoxic conditions. After silencing the HIF-1α gene, the sensitivities of LoVo MCS to all four chemotherapy drugs were restored. The apoptotic levels that all the drugs induced were all decreased to various extents in the hypoxic group. After silencing HIF-1α, the apoptosis level induced by all four chemotherapy drugs increased. The expression of HIF-1α and P-gp was significantly enhanced in LoVo MCS after treatment with hypoxia. Inhibiting HIF-1α significantly decreased the expression of MDR1/P-gp mRNA or protein in both the LoVo monolayers and LoVo MCS. The ChIP assay showed that HIF-1α was bound to the MDR1 gene promoter. Advanced colon carcinoma patients with expression of both HIF-1α and P-gp were more resistant to chemotherapy than that with non expression.ConclusionsHIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-gp. The expression of HIF-1α and MDR1/P-gp can be used as a predictive marker for chemotherapy resistance in colon cancer.
Highlights
Colon cancer is one of the most common malignant tumors throughout the world, and chemotherapy plays an important role in its treatment
Quantitative real-time PCR showed that the expression of HIF-1a was significantly higher in LoVo multicellular spheroids (MCS) than in LoVo monolayers, in hypoxic conditions and in normoxia (p,0.05) (Figure 1C)
Our previous study showed that HIF-1a protein expression is correlated with P-gp expression in colon carcinoma tissues and colon cancer cell lines, and HIF-1a and MDR1 mRNAs were found to be significantly higher in the same cells under hypoxic conditions than under normoxic conditions [12]
Summary
Colon cancer is one of the most common malignant tumors throughout the world, and chemotherapy plays an important role in its treatment. The tumor microenvironment plays a pivotal role in chemotherapy failure and drug resistance [2,3,4]. Hypoxia is a common feature of many malignant tumors, including colon cancer. Many studies have indicated that hypoxia potentiates tumor resistance to chemotherapy and radiotherapy [7,8], how the hypoxic microenvironment contributes to anticancer drug resistance has not yet been established. The correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) gene/transporter P-glycoprotein (P-gp) remains unclear. This study aims to explore the molecular mechanisms of reversing colon cancer MDR by focusing on the target gene HIF-1a
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