Study uncovers new mechanisms by which iron deficiency inhibits cell growth and proliferation

Researchers at Northwestern Medicine have unveiled novel insights into how iron deficiency can hinder cell growth and proliferation in eukaryotic cells, as outlined in their findings published in Nature Cell Biology. This study, led by Dr. Hossein Ardehali, has significant implications for advancing our understanding of anabolism (cell growth and proliferation) in both normal and pathological states, such as cancer, and may influence the development of new cancer therapies.

“In a broad context, we believe we’ve revealed a primitive iron-sensing pathway that’s shared among eukaryotes and linked it to the regulation of anabolism via the mTOR pathway,” explained Jason Shapiro, the lead author of the study and a member of the Medical Scientist Training Program (MSTP).

All eukaryotic cells necessitate a minimum threshold of iron to support anabolism, but the mechanisms governing how cells sense the necessary iron levels to regulate anabolic processes have been inadequately understood.

In a previous study from Dr. Ardehali’s lab, scientists established a connection between iron deficiency and anabolism through the inhibition of the mTOR (mammalian target of rapamycin) signaling pathway, a crucial metabolic hub within cells.

“mTOR responds to various growth factors, including amino acids and nucleotides. When it detects the presence of these nutrients in the environment, it triggers increased protein synthesis and enhances cellular anabolic processes,” elucidated Dr. Ardehali.

Building upon these prior findings, Dr. Ardehali’s team aimed to uncover the mechanisms by which iron deficiency inhibits the mTOR pathway in eukaryotic cells.

In their recent study, the team scrutinized various types of iron-deficient eukaryotic cells and the livers of mice subjected to an iron-deficient diet. Through this investigation, they detected widespread changes in histone methylation—a regulatory process that governs gene activation and deactivation—within these cells.

Notably, they identified KDM3B, an iron-binding enzyme, as an iron sensor that restrains mTOR activity through histone demethylation. Iron deficiency deactivates KDM3B, leading to the suppression of LAT3, an amino acid transporter, and RAPTOR, a conserved protein in the mTOR pathway.

“We believe that two pathways are responsible for the response to iron deficiency. One involves reducing a component of the mTOR complex, RAPTOR itself, and the other reduces leucine uptake within the cell. When intracellular leucine decreases, mTOR becomes less active,” elaborated Dr. Ardehali.

The researchers posit that reducing anabolism by diminishing iron levels could potentially be a treatment strategy for cancer, which relies on anabolism for its growth and proliferation.

“We believe that reducing iron in cancer cells could have synergistic effects in inhibiting cancer growth, particularly when combined with other chemotherapy agents. This is an avenue we hope to explore further, investigating the use of iron chelators as adjunct therapy alongside conventional chemotherapy to assess their potential benefits in cancer treatment,” Dr. Ardehali remarked.

Jason Shapiro expressed optimism about the future of research in this field, saying, “I believe we’ve only begun to scratch the surface in understanding how cells coordinate fundamental life processes with the levels of essential nutrients like iron and other metals. My hope is that our work will serve as a catalyst for future research in this intriguing area.”

Source: Northwestern University

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