brief notes - cancer vs. neurodegeneration, round 2 - ferroptosis

Last notes were about intracellular pH and senescent cell clearance, cancer and neurodegeneration. Just a few days later, an article on Nrf2 appeared in my news feed:

https://medicalxpress.com/news/2021-01-nrf2-magic-molecule-eternal-youth.html

"At the risk of overstating the obvious, if a little extra NRF2 is good for every cell in your body, and every cell in your body is good, then NRF2 must be good for your body. The weak link in that argument, however, is that all cells are not good. Nobody wants harmful bacterial cells to flourish, and nobody wants cancer cells to flourish. A paper recently published in Nature now suggests that inhibiting NRF2 can block the migration and invasion of non-small-cell lung cancer cells through the body. If anyone is going to derive benefit from NRF2, they may need to be smart about it.

The main reason NRF2, or Nuclear factor-erythroid 2-related factor 2, is so highly sought, is because it is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. Unfortunately, as the authors above have revealed, it also moonlights as an activator of the Rho-ROCK pathway, which promotes actin filamentation and movement of cells. The researchers were able to block this activity of NRF2 by giving an inhibitor known as brusatol."

The article also discusses ferroptosis - another phenomenon that pits cancer against neurodegeneration. Another news article by John Hewitt on ferroptosis:

https://medicalxpress.com/news/2020-01-life-constant-struggle-ferroptosis.html

A video presentation by Brent Stockwell, leading researcher on ferroptosis: https://youtu.be/cMjmzbOFewo

Review article by Stockwell et al. [2017]:

https://www.cell.com/cell/pdf/S0092-8674(17)31070-X.pdf

In the absence of glutamine, or when glutaminolysis is inhibited, cystine starvation and blockage of cystine import fail to induce the accumulation of reactive oxygen species (ROS), lipid peroxidation, and ferroptosis. This observation may be explained by the fact that α-ketoglutarate (αKG [alpha ketoglutarate]), a product of glutaminolysis, is required for ferroptosis (Gao et al., 2015).

Not all routes of glutaminolysis fuel ferroptosis, however. The first step of glutaminolysis involves conversion of glutamine into glutamate, a reaction catalyzed by the glutaminases GLS1 and GLS2. Although these enzymes are structurally and enzymatically similar, only GLS2 is required for ferroptosis (Gao et al., 2015). The GLS2 gene, but not GLS1, is a transcriptional target of the tumor suppressor p53, and upregulation of GLS2 contributes to p53-dependent ferroptosis (Jennis et al., 2016).

So here GSL2 is involved, but in manipulating pHi for senescent cell clearance and cancer cell sensitization, it's GS1 (and TTG for cancer).

pHi relates to cancer metabolism, the Warburg effect. A previous post on multicellularity and frataxin cited a source on frataxin reducing growth rate in colon cancer cells via stimulation of mitochondrial respiration. It turns out frataxin also decreases propensity to ferroptosis since it reduces free intracellular iron - so it looks like it could either promote or inhibit cancer, depending on the circumstances.

Identification of frataxin as a regulator of ferroptosis [2020]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068686/pdf/main.pdf 

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There's a review article on the general topic of cancer vs. neurodegeneration that I have on the 'to read' list:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519136/

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Alpha tocopherol prevents ferroptosis:

https://pubmed.ncbi.nlm.nih.gov/30110365/

"We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity."

I have wondered about the mechanism behind the risk modification for cancer and vitamin E supplementation by COMT genotype; is there some connection to ferroptosis?

https://pubmed.ncbi.nlm.nih.gov/30624689/