Alpha-1 antitrypsin (AAT) could have a preventive and therapeutic role in colitis-associated colon cancer (CAC), according to a new study published in the International Journal of Molecular Sciences.

The clinical relevance of AAT is well-illustrated by AAT deficiency (AATD), a rare genetic condition characterized by liver and obstructive lung disease.

“AAT and the small peptide AAT mimics are potent NSP [neutrophil-activated serine protease] inhibitors and may block NSP-induced IGFBP-3 [insulin-like growth factor binding protein-3] proteolysis, thereby restoring IGFBP-3′s antitumor and anti-inflammatory function in CAC,” the study’s authors said.


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AAT administration, in the form of Aralast, to a chronic dextran sulfate sodium colitis-azoxymethane mouse model reduced colonic inflammation, mucosa expansion, inflammatory cell infiltration, muscle thickening, and intramucosal adenocarcinoma formation compared with control animals. These findings suggest that AAT administration decreased the histological evidence of tissue damage and tumor growth, as well as inflammatory neutrophil/macrophage infiltration associated with CAC progression.

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Moreover, the results demonstrated that AAT administration could suppress the growth of established colon tumor. The underlying molecular mechanism involves the upregulation of IGFBP-3, which has known antitumor and anti-inflammatory functions, in colon tissue. The authors proposed that by inhibiting chronic colonic inflammation-induced NSP activity, AAT protects IGFBP-3 from NSP-mediated proteolysis and thereby restores IGFBP-3-mediated signaling pathway.

In addition, the authors found that AAT-treated mice had increased levels of total AAT in circulation but lower levels of nonfunctional oxidized AAT (Ox-AAT). Furthermore, the ratio of Ox-AAT over total AAT was decreased by up to 70%. Previous studies have shown that Ox-AAT lacks serine protease inhibitory activity and loses the ability to protect the lungs against neutrophil elastase.

Reference

Cai Q, Kim M, Harada A, et al. Alpha-1 antitrypsin inhibits tumorigenesis and progression of colitis-associated colon cancer through suppression of inflammatory neutrophil-activated serine proteases and IGFBP-3 proteolysis. Int J Mol Sci. 2022;23(22). doi:10.3390/ijms232213737