Chinese scientists discover new targets for sensitization of iron death

On December 27, 2022, Yang Minghua, professor of pediatrics at the Third Xiangya Hospital of Central South University, published original research results in Nature Communications, revealing a novel metabolic mechanism of tumor cells resistant to ferrozois and proposing a new strategy for targeting lipometabolic reprogramming sensitized iron death mediated by member 47 of the phospholipid transportase solic carrier family 47 (SLC47A1).

Professor Yang Minghua and Professor Daolin Tang of Texas Southwest Medical Center are the co-corresponding authors of the paper, Lin Zhi, a 2019 doctoral student in pediatrics of the Third Xiangya Hospital, is the first author, and the Third Xiangya Hospital is the first completion unit.

Induction of ferrozois is a new strategy for tumor treatment

The goal of tumor treatment is to remove tumor cells with less or no damage to normal cells. However, due to the existence of tumor drug resistance, tumor prevention and treatment are still full of challenges. Therefore, exploring the signaling pathways and molecular mechanisms of different cell death patterns can help to find new anti-tumor strategies or optimize existing treatment options.

Ferrosis was originally defined as a non-apoptotic form of cell death that selectively kills the oncogene RAS. At present, the industry believes that iron death is a regulatory necrosis-like cell death mode, and its occurrence and development mainly depends on intracellular iron ion aggregation and the production of a large number of lipid peroxides, which eventually leads to the disintegration and rupture of cell membranes.

In-depth discussion of the molecular mechanism and metabolic basis of ferrozois is expected to open up the application of ferrozois induction in tumor treatment. However, cancer cells can evade cellular ferrozois by activating or remodeling stress pathways, which limits the antitumor effects of ferrozotic inducers.

“We have long been committed to the study of the regulatory mechanism of leukemia and tumor cell death.” Yang Minghua, the corresponding author of the paper, said that the team found in a large number of studies in recent years that iron death may be another way to promote tumor death and overcome tumor drug resistance.

The picture shows Yang Minghua (middle) and team members carrying out relevant research work. Photo courtesy of interviewee

Abnormal lipid metabolism is one of the important features of cancer and is closely related to the occurrence and development of tumors. Lipids are oxidized substrates at the time of ferrozosis, and targeting lipid metabolism reprogramming to induce ferrozis is becoming a new idea for tumor treatment.

Phospholipid transportases are key molecules that transport phospholipids inside and outside cell membranes and are particularly important for maintaining membrane fluidity and intracellular lipid homeostasis. Abnormal expression and dysfunction of phospholipid transportases can cause lipid metabolism disorders and even lead to cell death.

“Although phospholipid transportase is involved in the regulation of apoptosis, it has not been reported whether phospholipid transportase regulates iron death.” Lin Zhi said that in this study, the team proposed to target a key target of lipid metabolism reprogramming, which can induce iron death to achieve the purpose of treating cancer, which provides a new idea for anti-cancer.

Discovery of iron dead lipid metabolism checkpoints

It is reported that there are about 49 known phospholipid transportases. In order to reveal the role of phospholipid transportase in ferrozoosis, Professor Yang Minghua’s team detected the expression changes of these 49 phospholipid transportases in multiple tumor cell lines induced to iron death, and found that SLC47A1 was the most significant phospholipid transportase upregulated during hemozosis in tumor cells, suggesting that SLC47A1 may be a key regulator of iron death.

The team further discovered through large-scale lipidomics analysis and in vitro and in vivo functional experiments that the “silent” SLC47A1 activates the synthase long-chain family member 4 (ACSL4)-sterol-O-acyltransferase 1 (SOAT1) signaling pathway, mediates the large accumulation of polyunsaturated fatty acid cholesterol esters in cells, and thus sensitizes ferrozois inducers (RSL3 or Erastin)-induced siderozoticism.

“The above results suggest that the phospholipid transportase SLC47A1 is a lipid metabolism checkpoint in the process of ferryosis, which is involved in maintaining intracellular cholesterol ester homeostasis and regulating hemozosis in tumor cells.” Yang Minghua said.

Yang Minghua work photo. Photo courtesy of interviewee

“We also found that a transcription factor with lipid regulation, peroxisome proliferator-activated receptor α (PPARA), positively regulates the expression of SLC47A1. Both PPARA and SLC47A1 deletion increase the sensitivity of cells to ferrous inducers, while overexpression of SLC47A1 reverses the sensitivity of PPARA-deficient cells to ferrozoosis. Yang Minghua said that this means that both PPARA and SLC47A1 are expected to become new targets for sensitizing tumor ferrozosis.

According to reports, this discovery also breaks the traditional understanding of the phospholipid transportase SLC47A1 in the academic community, not only revealing the new mechanism of SLC47A1-mediated iron death resistance, but also enriching the molecular biology theory of lipid metabolism.

Old drugs are newly used or become anti-cancer “new weapons”

It is reported that a new anti-cancer drug takes an average of 15 years from development to marketing, and requires a lot of effort and money. Therefore, the speed of new drug development is far from keeping up with the speed of tumor drug resistance; The high cost of research and development also leads to the fact that new anti-cancer drugs are often expensive, which is often unaffordable for ordinary people.

“Can we sift out some cheap and useful drugs from existing drugs?” This is a question that Yang Minghua has repeatedly pondered.

When Yang Minghua was looking for an inhibitor for SLC47A1, a commonly used clinical drug, cimetidine, attracted his attention.

As a selective H2 receptor blocker, cimetidine is a commonly used anti-nausea and gastric medicine, and is mainly used clinically for the treatment of gastric and duodenal ulcers and upper gastrointestinal bleeding.

“Cimetidine is also a recognized selective SLC47A1 inhibitor.” Yang Minghua said that in view of the negative regulation of ferrozois function of SLC47A1, the team speculated that cimetidine and ferrozotic inducers can synergistically exert anti-tumor effects.

At present, Yang Minghua’s team has preliminarily confirmed the synergistic anti-tumor effect of cimetidine and the iron death inducer IKE on a mouse subcutaneous transplant tumor model. Subsequently, the team will construct a transplanted tumor model derived from tumor patients to further verify the anti-tumor effect of cimetidine, which is expected to lay a solid foundation for the clinical transformation of this study and provide a strong basis for the “old drug new use” of cimetidine in the field of tumors.

Yang Minghua also hopes to clinically verify the use of cimetidine to target sensitized tumor cell ferrozis as soon as possible. “Compared with the time and money cost of developing a new drug, a cheap and effective old drug may be more urgently needed by patients.”

The reviewers also agreed that this is a well-structured and technically reliable study, which provides strong evidence for the metabolic pathway to regulate the sensitivity of iron death; The study elucidates a plausible mechanism and potential direction for exploiting the discovery of sensitivity of therapeutic cancer cells to the pharmacological induction of iron death; The research results are novel and of great significance and value in the field of iron death.

The research was supported by the National Natural Science Foundation of China and the Third Xiangya Hospital Huizhi Education Project. (Source: Wang Haohao, China Science News)

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