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bioRxiv · 10.1101/2025.02.27.640554

Methionine dependence in cancer cells due tolack of B12-dependent methionine synthase activity

El Husseiny, M.·Nilsson, R.
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Abstract

Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown. Here, we report evidence that methionine dependence is caused by low MTR activity secondary to a B12 deficiency. High levels of the B12 cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted "revertant" cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B12-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B12-dependent human enzyme had no effect. These data establish a biochemical basis for the long-standing question of methionine dependence in cancer, and may open up new avenues for exploiting the phenomenon for cancer therapy.

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El Husseiny, M., Nilsson, R.. 2025-02-27. Methionine dependence in cancer cells due tolack of B12-dependent methionine synthase activity. https://doi.org/10.1101/2025.02.27.640554

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