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A novel target in colitis-associated cancer
Gobert A, Latour Y, Asim M, et al. Protective role of spermidine in colitis and colon carcinogenesis. Gastroenterology 2022;1623:813–27; doi:10.1053/j.gastro.2021.11.005.
Polyamines are found in all mammalian cells and include putrescine, spermine and spermidine. The enzyme spermine oxidase (SMOX) catalyses the conversion of spermine to spermidine. The role of polyamines in colorectal carcinogenesis is unclear to date.
Gobert et al previously reported that SMOX knockout mice have low levels of spermidine and develop more severe dextran sulfate sodium (DSS)-induced colitis. In this paper they found that patients with UC had lower SMOX messenger RNA levels in colonic tissue and the levels were inversely correlated with disease severity. Immunostaining showed reduced SMOX in the colonic epithelial cells of patients with high-grade dysplasia. Treatment of SMOX−/− mice with spermidine led to increased spermidine in the colon but not putrescine or spermine, as measured by mass spectrometry. Spermidine treatment ameliorated DSS colitis in both wild type (wt) and SMOX−/− mice.
In an azoxymethane (AOM)-DSS model of colitis-associated cancer, SMOX−/− mice developed more severe disease, and again this was improved by spermidine treatment in terms of tumour size and burden. Spermidine treatment also reduced tumour burden in an adenomatous polyposis coli (APC) knockout sporadic model of colon cancer. RNA sequencing of colonic mucosa showed increased alpha-defensin expression in SMOX−/− mice and in both SMOX−/− and wt mice with AOM-DSS treatments, which was reduced by spermidine supplementation. This was confirmed by reverse transcription PCR and immunostaining. There was a resulting dysbiosis of the microbiome, which was restored with spermidine.
Gobert et al conclude that polyamines may have a dichotomous role in colorectal cancer. Spermidine appears to protect against colitis and colitis-associated cancer and could be considered a chemopreventive therapy.
Genes + microbiome + diet + disease = much more to discover
Qin Y, Havulinna A, Liu Y et al. Combined effects …
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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