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Controversy about pharmacological modulation of Nrf2 for cancer therapy
Lidija Milkovic1, Neven Zarkovic1, Luciano Saso2
1Laboratory for Oxidative Stress, LabOS, Rudjer Boskovic Institute, Bijenicka 54, HR-10000 Zagreb, Croatia.
Abstract:
Conventional anticancer therapies such as radiotherapy and chemotherapies are associated with oxidative stress generating reactive oxygen species (ROS) and reactive aldehydes like 4-hydroxynonenal in cancer cells that govern them to die. The main mechanism activated due to exposure of the cell to these reactive species is the Nrf2-Keap1 pathway. Although Nrf2 was firstly perceived as a tumor suppressor that inhibits tumor initiation and cancer metastasis, more recent data reveal its role also as a pro-oncogenic factor. Discovery of the upregulation of Nrf2 in different types of cancer supports such undesirable pathophysiological roles of Nrf2. The upregulation of Nrf2 leads to activation of cytoprotective genes thus helping malignant cells to withstand high levels of ROS and to avoid apoptosis, eventually becoming resistant to conventional anticancer therapy. Therefore, new treatment strategies are needed for eradication of cancer and in this review, we will explore two opposing approaches for modulation of Nrf2 in cancer treatments.
Insights
Conventional cancer therapies induce oxidative stress, activating the Nrf2-Keap1 pathway. While initially seen as a tumor suppressor, Nrf2 now appears pro-oncogenic, aiding cancer cell survival and therapy resistance, necessitating new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Conventional cancer treatments like chemotherapy and radiotherapy induce oxidative stress, generating reactive oxygen species (ROS) and reactive aldehydes.
- The Nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is a primary cellular defense mechanism activated by oxidative stress.
- Emerging evidence indicates that Nrf2, initially considered a tumor suppressor, functions as a pro-oncogenic factor in established cancers.
Purpose of the Study:
- To review the dual role of the Nrf2-Keap1 pathway in cancer.
- To explore opposing strategies for modulating Nrf2 activity in cancer treatment.
- To highlight the need for novel therapeutic approaches targeting Nrf2.
Main Methods:
- Literature review of studies investigating the Nrf2-Keap1 pathway in cancer.
- Analysis of the pathophysiological roles of Nrf2 in cancer development and progression.
- Examination of therapeutic strategies targeting Nrf2 modulation.
Main Results:
- Nrf2 upregulation is observed in various cancer types, promoting malignant cell survival.
- Activated Nrf2 enhances the expression of cytoprotective genes, conferring resistance to oxidative stress and apoptosis.
- This resistance contributes to therapeutic failure in conventional anticancer treatments.
Conclusions:
- The Nrf2-Keap1 pathway plays a complex, context-dependent role in cancer, acting as both a suppressor and promoter.
- Targeting Nrf2 presents a promising avenue for cancer therapy, with potential for both inhibition and activation strategies.
- Further research is needed to develop effective Nrf2-modulating therapies for cancer eradication.