【Adv. Sci】Shandong University Chubo and other teams discovered a novel anti-ferrozotic pathway that promotes tumor cell growth

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Written by Sophia

It is known that the conversion of methionine to cysteine can protect tumor cells from iron death
during cysteine starvation through transamination.
However, whether metabolites produced by amino acids are involved in ferrozois independently of
the cysteine pathway is largely unknown.

Recently, Chubo of Shandong University, Chai Renjie of Southeast University/Nantong University/University of Electronic Science and Technology of China and Yin Chengqian of Shenzhen Bay Laboratory published a research paper entitled "Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth" in Advanced Science.
This study showed that the tryptophan metabolites serotonin (5-HT) and 3-hydroxyanthranilic acid (3-HA) significantly help tumor cells escape ferrozois, unlike
cysteine-mediated inhibition of ferrozozois.

https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202204006

Research background

 01 

Ferrozosis is a newly discovered programmed cell death, distinct from apoptosis and n3-hydroxyanthranilate 3,4-dioxygenase (HAAO) necrosis
.
Initiation of iron dead cell death is induced by phospholipid peroxide accumulated in an iron-dependent manner
.
Lipid hydroperoxides (PUFA-OOH) are converted to non-toxic lipid alcohols (PUFA-OH) by glutathione peroxidase 4 (GPX4), ferrozolosin 1 (FSP1), tetrahydrobioptrexin (BH4)
system, or the newly identified dihydroorotic acid dehydrogenase (DHODH).
Emerging evidence suggests that ferrozosis is associated
with cancer immunotherapy and tumor suppression.
Of the four identified antiferrozotic pathways, the GPX4-GSH pathway dominates in defending nephrozois in cancer cells
.

Cysteine has been shown to inhibit iron death (GSH) through biosynthesis of glutathione, a substrate for GPX4 to reduce oxidative lipids, and the source of cysteine is largely dependent on extracellular uptake and de novo biosynthesis
.
Solute carrier family member 7 member 11 (SLC7A11) is a catalytic subunit of the cystine/glutamate antitransport system xc−(SLC7A11/SLC3A2) and is the main plasma membrane transporter
of extracellular cystine.
Intracellular cystine is rapidly reduced to cysteine, which is subsequently used in glutathione synthesis
.
GPX4 eliminates lipid hydroperoxides
by utilizing GSH to protect cells from membrane lipid peroxidation.
Thus, blocking SLC7A11-mediated cystine uptake by cystine starvation or Erasstine treatment sensitizes cells to
iron death.
In the case of cystine starvation or cystine deficiency, some tumor cells can defend against ferrozosis
by converting methionine to cysteine through the transaminatory pathway.
A growing body of research suggests that some other amino acids such as glutamate and glutamine are involved in ferrozois
through cysteine-related pathways.
However, what is less known is whether metabolites derived from amino acids affect the iron death sensitivity of tumor cells, independent of cysteine-mediated iron death
.

Study results

 02 

Studies have shown that the tryptophan metabolites serotonin (5-HT) and 3-hydroxyanthranilic acid (3-HA) significantly promote tumor cell escape from ferrozoosis, unlike
cysteine-mediated inhibition of ferrozoticosis.
Mechanistically, both 5-HT and 3-HA act as potent free radical trapping antioxidants (RTAs) to eliminate lipid peroxidation, thereby inhibiting iron dipping cell death
.
Monoamine oxidase A (MAOA) significantly eliminates the protective effect
of 5-HT by degrading 5-HT.
The lack of MAOA makes cancer cells resistant to iron death after 5-HT treatment
.
Canine urease (KYNU) is essential for the production of 3-HA, conferring cells resistance to iron apoptotic cell death, while 3-hydroxyanthranilase 3,4-dioxygenase (HAAO) significantly blocks 3-HA-mediated hemozozois inhibition
by consuming 3-HA.
In addition, expression levels of HAAO were positively correlated
with lipid peroxidation and clinical outcomes.

5-HT-mediated resistance to iron death is not associated with typical anti-iron death pathways

Together, these findings suggest that tryptophan metabolism promotes tumor growth as a new antiferrotic pathway, and that targeting this pathway would be a promising treatment for cancer treatment
.

Resources:

https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202204006

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.