Trypsinogen and chymotrypsinogen: potent anti-tumor agents

González-Titos, Aitor; Hernández-Camarero, Pablo; Barungi, Shivan; Marchal, Juan A.; Kenyon, Julian; Perán, Macarena

doi:10.1080/14712598.2021.1922666

Cited by 6 publications

(5 citation statements)

References 101 publications

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“…Trypsin is closely related to inflammatory reaction ( González-Titos et al, 2021 ). Since the 1960s, trypsin inhibitors have been used clinically to repair tissue for they can solve the inflammatory response ( Shah and Mital, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

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Trypsin inhibitor LH011 inhibited DSS-induced mice colitis via alleviating inflammation and oxidative stress

Jia

Wang

Xu³

et al. 2022

Front. Pharmacol.

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Background: Ulcerative colitis (UC) is one type of inflammatory bowel disease, characterized by inflammation with infiltration and activation of macrophages in colonic tissue. LH011 is a trypsin inhibitor with potential anti-inflammatory effect.Purpose: Here, we aim to assay the effects of LH011 on UC and further investigate the potential mechanisms in vitro and in vivo.Methods: Dextran sulfate sodium (DSS, 3.5%, w/v) was used to induce UC, and lipopolysaccharide (LPS) was used to induce inflammation in RAW 264.7 cells. LH011 was administrated to mice in vivo or to RAW 264.7 cells in vitro at different concentrations. The cytokines (IL-1β, IL-6, and TNF-α) and the changes of NF-κB and Nrf2 pathways were detected.Results: The results showed that LH011 improved DSS-induced mice colitis, including loss of weight, disease activity index (DAI), and colonic pathological damage. In addition, LH011 inhibited the expressions of IL-1β, IL-6, and TNF-α and strengthened the anti-oxidative capacity. Mechanically, LH011 downregulated the nuclear localization of NF-κB p65 and upregulated the protein expression of Nrf2.Conclusion: These results demonstrated that LH011 alleviated inflammation and oxidative stress during UC by inhibiting TLR4/NF-κB and activating Nrf2/Keap1/HO-1 signaling pathways.

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Section: Resultsmentioning

confidence: 99%

“…Trypsin prefers to activate protease-activated receptor 2 (PAR2) ( González-Titos et al, 2021 ). Activated PAR2 regulates many signaling pathways involving in the pathogenesis of inflammatory disorders, such as the NF-κB pathway ( Banfi et al, 2009 ).…”

Section: Disscusionmentioning

confidence: 99%

Trypsin inhibitor LH011 inhibited DSS-induced mice colitis via alleviating inflammation and oxidative stress

Jia

Wang

Xu³

et al. 2022

Front. Pharmacol.

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“…Pancreatic cancer cells express around 20% of chymotrypsin C normal cells expression, with this enzyme participating in cancer cell apoptosis and migration [42]. A recent report suggested that a combination of trypsinogen and chymotrypsinogen displayed anti-tumorigenic potential [43].…”

Section: Discussionmentioning

confidence: 99%

A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment

Pérez-Díez

Andreu

Hidalgo

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) prognosis and treatment response remains devastatingly poor due partly to the highly heterogeneous, aggressive, and immunosuppressive nature of this tumor type. The intricate relationship between stroma, inflammation, and immunity remains vaguely understood in the PDAC microenvironment. Here, we performed a meta-analysis of stroma-, and immune-related gene expression in the PDAC microenvironment to improve disease prognosis and therapeutic development. We selected twenty-one PDAC studies from the Gene Expression Omnibus and ArrayExpress databases, including 922 samples (320 controls and 602 cases). Differential gene enrichment analysis identified 1153 significant dysregulated genes in PDAC patients that contribute to a desmoplastic stroma and an immunosuppressive environment (the hallmarks of PDAC tumors). The results highlighted two gene signatures related to the immune and stromal environments that cluster PDAC patients in high- and low-risk groups, impacting patient stratification and therapeutic decision-making. Moreover, HCP5, SLFN13, IRF9, IFIT2, and IFI35 immune genes were related to prognosis value in PDAC patients, for the first time.

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“…Other studies have reported that that trypsin in vitro can exert antitumor activity on different tumor cell lines by suppressing the EMT program and promoting cancer cell differentiation [ 30 , 31 ]. A combination of trypsinogen and chymotrypsinogen inhibited tumor growth, invasion and angiogenesis both in vitro and in vivo and demonstrated clinical efficacy on a cohort of 46 patients with advanced tumors of different origin [ 32 , 33 ]. Nevertheless, because of its complex activities, trypsin is not suitable for therapeutic purposes, and its proteolytic activity has to be tightly regulated to avoid tissue damage [ 34 ], inflammation, and even chronic pancreatitis and consequently PDAC [ 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth

Resovi,

Persichitti,

Brunelli

et al. 2023

J Exp Clin Cancer Res

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Background The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches. Methods and results Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transplanted orthotopically with pancreatic ductal adenocarcinoma (PDAC) in mouse pancreas inhibited tumor growth. The effect was mediated by trypsin-generated fibronectin (FN) fragments released by pancreatic spheroids. Tumor inhibition was observed also in a model of acute pancreatitis associated with trypsin activation. Mass spectrometry proteomic analysis of fragments and mAb against different FN epitopes identified the FN type III domain as responsible for the activity. By inhibiting integrin α5β1, FAK and FGFR1 signaling, the fragments induced tumor cell detachment and reduced cell proliferation. Consistent with the mutual relationship between the two pathways, FGF2 restored both FGFR1 and FAK signaling and promoted PDAC cell adhesion and proliferation. FAK and FGFR inhibitors additively inhibited PDAC growth in vitro and in orthotopic in vivo models. Conclusions This study identifies a novel role for pancreatic trypsin and fibronectin cleavage as a mechanism of protection against cancer by the pancreatic microenvironment. The finding of a FAK-FGFR cross-talk in PDAC support the combination of FAK and FGFR inhibitors for PDAC treatment to emulate the protective effect of the normal pancreas against cancer.

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Trypsinogen and chymotrypsinogen: potent anti-tumor agents

Cited by 6 publications

References 101 publications

Trypsin inhibitor LH011 inhibited DSS-induced mice colitis via alleviating inflammation and oxidative stress

Trypsin inhibitor LH011 inhibited DSS-induced mice colitis via alleviating inflammation and oxidative stress

A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment

Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth

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