Abstract:
Altered expression of cellular redox genes and proteins contributes to invasion, metastasis, and drug resistance in cancer. NADPH oxidase (NOX) isoforms are the pro_oxidant enzymes that generate ROS as a primary product. Dysregulation of NOX activity and expression alters ROS generation, which either directly or indirectly modulates cell death and survival signaling during the progression of cancer. Nuclear factor erythroid 2_related factor 2 (Nrf_2) is an inducible transcription factor, which transcribes an array of antioxidant genes and protects cancer cells from the oxidative stress. Both NOXs and Nrf_2 participate in the regulation of cellular redox homeostasis; but their dysregulation promotes oxidative stress, which contributes to the progression of different types of cancer. Indeed, the role of NOX isoforms and Nrf_
2 in developing the drug resistance in cancer is largely unknown. In the present study, we have explored the association of NOX isoforms and Nrf_2 signaling with the MDR1 gene expression in colon carcinoma cells (HCT_116/R). The MDR1 gene was overexpressed to develop resistant HCT_116/R cells and the NOX activation and ROS generation were monitored. We also assessed the role of NOX isoforms and Nrf_2 in the 5_fluorouracil (5_FU) mediated apoptotic cell death of HCT_116/R cells. The HCT_116/R cells demonstrated higher expression of HIF_1α, Nrf_2, and HO_1 and were highly resistant to 5_ FU; they also displayed upregulated expression and activity of NOX_2, as well as elevated ROS levels. Interestingly, the treatment with HDC, a specific NOX_2 inhibitor, reduced the ROS levels in HCT_116/R cells. The treatment with HDC
and ML_385 (specific inhibitor of Nrf_2) augmented the 5_FU_mediated apoptotic cell death of HCT_116/R cells, which suggests that NOX_2 and Nrf_2 are involved in the development of the chemoresistant phenotype of these cells. Taken together, NOX_2 and Nrf_2 are associated with developing drug resistance of colorectal cancer cells and might be potential targets to overcome drug resistance during cancer therapy
