Alpha-1 Antitrypsin Inhibits Tumorigenesis and Progression of Colitis-Associated Colon Cancer through Suppression of Inflammatory Neutrophil-Activated Serine Proteases and IGFBP-3 Proteolysis

Abstract

Colitis-associated colon cancer (CAC) accompanies the massive infiltration of neutrophils during tumorigenesis and progression of CAC. Depletion of neutrophils in circulation results in significant inhibition of tumor incidence in CAC. However, the underlying mechanisms are largely unclear. In this study, we provide evidence for the crucial involvement of inflammatory neutrophil-activated serine proteases (NSPs) on the dysregulation of the anti-inflammatory and antitumor IGFBP-3/IGFBP-3R signaling axis in CAC using a chronic AOM/DSS mouse model. We also provide preclinical evidence for α1-antitrypsin (AAT) as a preventive and as a therapeutic for CAC. AAT administration not only prevented colitis-associated tumorigenesis but also inhibited established CAC. AOM/DSS treatment results in the significant activation of NSPs, leading to CAC through increased pro-inflammatory cytokines and decreased anti-inflammatory and antitumor IGFBP-3. Collectively, these data suggest that the NSPs proteolyze IGFBP-3, whereas AAT inhibits chronic colonic inflammation-induced NSP activity and subsequently suppresses IGFBP-3 proteolysis. Therefore, the anti-inflammatory and antitumor functions of the IGFBP-3/IGFBP-3R axis are restored. AAT mimicking small peptides also showed their inhibitory effects on NSP-induced IGFBP-3 proteolysis. These results suggest that targeting the NSP-IGFBP-3/IGFBP-3R axis using NSP inhibitors such as AAT and the AAT mimics and IGFBP-3R agonists could lead to novel approaches for the prevention and treatment of CAC.

Beneficial effects of alpha-1 antitrypsin therapy in a mouse model of colitis-associated colon cancer

“…In fact, a short while ago Qing Cai, and co-authors reported that CRC development in colitis associated AOM/DSS mouse model is characterized by neutrophilic inflammation, oxidative stress, and increased serine protease activity. Furthermore, the authors demonstrated that augmentation therapy with AAT (commercial preparation, Aralast NP) suppresses inflammatory response and proteolysis and inhibits cancer progression [ 40 ].…”

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions

“…While those with AAT deficiency due to the PiZZ genotype are at risk of liver cancer, this is likely due to the accumulation of Z-AAT polymers causing liver inflammation and cirrhosis that progressed to cancer, i.e., a toxic gain of function. Neutrophil-associated inflammation may also help drive tumorigenesis that may be inhibited by AAT [92]. Interestingly, the gene that encodes TMPRSS2 is also androgen-responsive and a TMPRSS2 gene fusion with ETS transcription factors (such as v-ets erythroblastosis virus E26 oncogene homolog) results in the TMPRSS2:ERG gene product that is increasingly recognized to be involved in prostate carcinogenesis [93,94].…”

Pentosan Polysulfate Affords Pleotropic Protection to Multiple Cells and Tissues

“…Lung mucosal tissues also have a number of serpin protease inhibitors which afford tissue protection, and these include elafin, SLPI and α1-protease inhibitor. Heparin and HS enhance this tissue-protective effect; α1-protease inhibitor and members of the superfamily not only have tissue-protective roles in lung tissues but are also potent protective agents in the gut [ 143 , 146 ], and their interactions with heparin and HS further improve their protease inhibitory properties. A group of novel protease inhibitors, the siropins, are also supplied by the gut microbiome and these have tissue-protective properties [ 145 , 147 ].…”