Science Advances: Another breakthrough in iron death, revealing fatal flaws in solid tumors

Solid tumors rely on blood supply to deliver oxygen and nutrients
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As the tumor grows, these blood vessels cannot provide oxygen and nutrients to every part of the tumor, resulting in hypoxia in the area

Carbonic anhydrase is a kind of metalloenzyme, of which IX and XII (CAIX/XII) are pH adjusting enzymes induced by hypoxia, which can catalyze the reversible hydration of carbon dioxide into bicarbonate and protons
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CAIX also plays a key role in the survival, invasion and metastasis of cancer cells

Regulated cell death is a key determinant of the success of cancer treatment
.

Hypoxia enriches cells that are resistant to apoptosis

On August 27, 2021, a research team from the British Columbia Cancer Institute in Canada published a titled Genome-wide synthetic lethal screen unveiling novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid in Science Advances.
Research papers on tumors
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The study found that the pH regulator carbonic anhydrase IX (CAIX), which is induced by tumor hypoxia, can prevent iron death of cancer cells, confirming the molecular mechanism by which CAIX regulates cell survival
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This discovery will help researchers develop new strategies for the treatment of solid tumors

In January 2021, the World Health Organization (WHO) International Agency for Research on Cancer (IARC) released the latest global cancer burden data for 2020
.

The latest estimated data shows that in 2020, 19.

The top ten cancer types with the number of new cancer cases in 2020

The research team conducted an unbiased, genome-wide CAIX synthetic lethal CRISPR screen in hypoxic triple-negative breast cancer (TNBC) cells to identify genes that interact with CAIX
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Genes affected by CA9 deletion are significantly enriched in RNA metabolism, nonsense-mediated decay, ribosomal RNA processing, selenocysteine ​​synthesis, selenoamino acid metabolism, tricarboxylic acid (TCA) cycle, and electron transport pathways

Next, the research team stained a small breast tumor tissue microarray consisting of a triple-negative breast cancer cohort and found that CAIX was expressed in about 65% of the cases in the array, while NFS1 was expressed in almost all cases
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The above data indicate that CAIX and NFS1 are expressed in a subset of breast cancer patients, so co-targeting may be beneficial to patients
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So the research team knocked out CA9 and NFS1 in TNBC cancer cells at the same time, and found that the iron level of the cells increased, accompanied by increased lipid peroxidation, which is a sign of iron death, indicating that the cancer cells are double knocked out after CAIX and NFS1.

The research team next tried to evaluate whether the combination of CAIX/XII inhibition with limiting cystine availability (a substrate of NFS1) would lead to enhanced iron death by inhibiting the cystine-glutamate antiporter xCT
.

CAIX/XII inhibition itself rarely leads to cell death

Subsequently, the research team jointly targeted CAIX/XII and xCT in clinically relevant models.
Similar to the findings in cell line models, this combination resulted in a significant increase in organoid cell death from multiple patients, which is better than using either alone Compound therapy
.
Therefore, co-targeting CAIX/XII and xCT will enhance iron death, which is an effective strategy for pharmacologically using the synthetic lethal interaction between CAIX and NFS1
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In the in-depth molecular mechanism study, the research team found that CAIX inhibitors caused the acidification of pHi.
The bicarbonate produced by CAIX/XII was imported through bicarbonate transporters to protect cells from iron death, indicating that pHi regulation is regulating iron death.
Medium is very important
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AMPK signaling is essential for maintaining metabolic homeostasis.
After co-targeting CAIX/XII and xCT, the research team observed AMPK inactivation.
This inactivation echoes the reduction of AMPK target ACC1 phosphorylation, indicating that the combination therapy is working Activate ACC1, which leads to increased iron death
.
The above data also implies the importance of AMPK/ACC1/ACSL4 axis in co-targeting the downstream of hypoxia-induced CAIX and xCT
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All in all, this work identified a novel synthetic lethal interaction between CAIX and NFS1.
The inhibition of xCT and CAIX/XII inhibition is a very effective alternative to pharmacologically utilize this synthetic lethal interaction
.
The research made people realize that CAIX plays an important role in redox homeostasis and prevention of iron death through pH adjustment, and will help researchers develop new strategies for the treatment of solid tumors
.

Original source:

Original source:

Shawn C.
Chafe, et al.
Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors .
Science Advances 27 Aug 2021: Vol.
7, no.
35, eabj0364.
DOI: 10.
1126 /sciadv.
abj0364.

Genome-wide synthetic lethal screen unveils novel CAIX-NFS1 / xCT axis as a targetable vulnerability in hypoxic solid tumors in this message