Colorectal cancer is one of the most common cancer and the third leading cause of death worldwide. Increased generation of reactive oxygen species (ROS) is observed in many types of cancer cells. Several studies have reported that an increase in ROS production could affect the expression of proteins involved in ROS-scavenging, detoxification and drug resistance. Nuclear factor erythroid 2 related factor 2 (Nrf₂) is a known transcription factor for cellular response to oxidative stress. Several researches exhibited that Nrf₂ could exert multiple functions and expected to be a promising therapeutic target in many cancers. Here, Nrf₂ was knocked down in colorectal cancer cell line HT29 and changes that occurred in signaling pathways and survival mechanisms were evaluated.

The influence of chemotherapy drugs (doxorubicin and cisplatin), metastasis and cell viability were investigated. To explore the association between specific pathways and viability in HT29-Nrf₂⁻, proteomic analysis, realtime PCR and western blotting were performed.

In the absence of Nrf₂ (Nrf₂⁻), ROS scavenging and detoxification potential were dramatically faded and the HT29-Nrf₂⁻ cells became more susceptible to drugs. However, a severe decrease in viability was not observed. Bioinformatic analysis of proteomic data revealed that in Nrf₂⁻ cells, proteins involved in detoxification processes, respiratory electron transport chain and mitochondrial-related compartment were down regulated. Furthermore, proteins related to MAPKs, JNK and FOXO pathways were up regulated that possibly helped to overcome the detrimental effect of excessive ROS production.

Our results revealed MAPKs, JNK and FOXO pathways connections in reducing the deleterious effect of Nrf₂ deficiency, which can be considered in cancer therapy.