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NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis

Mara Cirone¹, Gabriella D'Orazi^2,3

¹Department of Experimental Medicine, University of Rome La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.

International Journal of Molecular Sciences

|January 8, 2023

Abstract:

Expanding knowledge of the molecular mechanisms at the basis of tumor development, especially the cross-talk between oncogenic pathways, will possibly lead to better tailoring of anticancer therapies. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in cancer progression, not only because of its antioxidant activity but also because it establishes cross-talk with several oncogenic pathways, including Heat Shock Factor1 (HSF1), mammalian target of rapamycin (mTOR), and mutant (mut) p53. Moreover, the involvement of NRF2 in gammaherpesvirus-driven carcinogenesis is particularly interesting. These viruses indeed hijack the NRF2 pathway to sustain the survival of tumor cells in which they establish a latent infection and to avoid a too-high increase of reactive oxygen species (ROS) when these cancer cells undergo treatments that induce viral replication. Interestingly, NRF2 activation may prevent gammaherpesvirus-driven oncogenic transformation, highlighting how manipulating the NRF2 pathway in the different phases of gammaherpesvirus-mediated carcinogenesis may lead to different outcomes. This review will highlight the mechanistic interplay between NRF2 and some oncogenic pathways and its involvement in gammaherpesviruses biology to recapitulate published evidence useful for potential application in cancer therapy.

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) impacts tumor development through its antioxidant role and interactions with oncogenic pathways. Manipulating NRF2 offers potential for novel cancer therapies, especially in gammaherpesvirus-related cancers.

Area of Science:

Oncology
Molecular Biology
Virology

Background:

Nuclear factor erythroid 2-related factor 2 (NRF2) is crucial in cancer progression.
NRF2 interacts with oncogenic pathways like Heat Shock Factor 1 (HSF1), mammalian target of rapamycin (mTOR), and mutant p53.
NRF2 plays a role in gammaherpesvirus-induced carcinogenesis.

Purpose of the Study:

To review the mechanistic interplay between NRF2 and oncogenic pathways.
To explore NRF2's involvement in gammaherpesvirus biology and carcinogenesis.
To highlight potential therapeutic applications of NRF2 pathway manipulation in cancer.

Main Methods:

Literature review of published evidence.
Analysis of molecular mechanisms underlying NRF2's role in cancer.
Examination of NRF2's interaction with gammaherpesviruses.

Main Results:

NRF2's antioxidant activity and cross-talk with oncogenic pathways influence tumor development.
Gammaherpesviruses exploit the NRF2 pathway for tumor cell survival and evasion of treatment-induced oxidative stress.
NRF2 activation can prevent gammaherpesvirus-driven oncogenic transformation, suggesting context-dependent outcomes.

Conclusions:

Understanding NRF2's complex role in cancer and viral carcinogenesis is key for developing targeted therapies.
Modulating the NRF2 pathway presents a promising strategy for anticancer treatment.
Further research into NRF2's interplay with oncogenic pathways and viruses can refine therapeutic approaches.

Read full analysis

Keywords:

KEAP1 NFkB NRF2 STAT3 apoptosis autophagy cancer therapy chemoresistance gammaherpesviruses inflammation mTOR oxidative stress p21 p53 p62/SQSTM1 reactive oxygen species (ROS)

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