NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression

Abstract

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators.

ATF4‐dependent increase in mitochondrial‐endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

“…This may aid to explain why TUDCA treatment (Figure 2W‐Z) impairs ATF4 expression in control cells and attenuates its induction upon OPA1 loss. Beyond XBP1, NRF2, another transcription factor induced by OPA1 deletion, plays pleiotropic roles in mitochondrial biology (Buttari et al, 2022). CHOP which is induced during ER stress might trigger mitochondria‐dependent apoptosis (Hu et al, 2019).…”

ATF4 Dependent Increase in Mitochondrial-Endoplasmic Reticulum Tethering Following OPA1 Deletion in Skeletal Muscle

“…Similarly, in neuroblastoma models, IRE1α-XBP1 inhibition decreases MERC spaces (Chu et al, 2021). NRF2, another transcription factor induced by OPA1 deletion, plays pleiotropic roles in mitochondrial biology (Buttari et al, 2022). CHOP which is induced during ER stress might trigger mitochondria-dependent apoptosis (Hu et al, 2019).…”

Mitochondria: It is all about energy

“…PGC1α, in collaboration with NRF2, increases mitochondrial biogenesis to supply healthier mitochondria. NRF2 further supports the maintenance of the mitochondrial membrane potential, OXPHOS, ATP synthesis, fatty acid synthesis, and oxidation ( Buttari et al, 2022 ).…”

“…This decreases the expression of pro-inflammatory mediators and increases the detoxifying capacity of all cell types. ARE sequences (5′-RTGACnnnGC-3′) are present in more than 200 genes, such as those that express antioxidant enzymes, NAD(P)H quinone oxidoreductase 1 (NQO1), sulfiredoxin 1 (SRXN1), glutathione S-transferase (GST), health-preserving red blood cells heme oxygenase-1 (HMOX1), multidrug resistance-associated proteins (MRP), and UDP-glucuronosyltransferase (UGT) ( Buttari et al, 2022 ).…”