Trypsin is produced by and activates protease-activated receptor-2 in human cancer colon cells

Ducroc, Robert; Bontemps, C.; Marazova, Katia; Devaud, Hélène; Darmoul, Dalila; Laburthe, Marc

doi:10.1016/s0024-3205(01)01519-3

Cited by 43 publications

(28 citation statements)

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“…This mechanism may contribute in the well-known ability of trypsin to facilitate cancer growth and diffusion. 38 In conclusion, we have demonstrated that potentiation of PAR-2 activation induces neovascularization in skeletal muscles. The present study provides new insights into the vascular action of PAR-2.…”

Section: Discussionmentioning

confidence: 61%

“…36 Present data clearly showing that PAR-2 activation results in angiogenesis may provide possible interpretation for the finding that receptor expression is upregulated in the tumor environment. 37,38 Trypsin, secreted by malignant cells into the extracellular space, may activate vascular PAR-2 in the vicinity of the tumor, thus promoting tumoral angiogenesis. This mechanism may contribute in the well-known ability of trypsin to facilitate cancer growth and diffusion.…”

Section: Discussionmentioning

confidence: 99%

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Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Milia

Salis

Stacca

et al. 2002

Circulation Research

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Abstract-Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH 2 ) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH 2 ) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Milia

Salis

Stacca

et al. 2002

Circulation Research

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“…The levels of trypsin, a potent and physiological activator of PAR2, are elevated in gastric, colon, ovarian and lung tumors (Ducroc et al, 2002). TF is also linked to cancer progression (Belting et al, 2005).…”

Section: Pars and Cancermentioning

confidence: 99%

Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer

Arora

Ricks

Trejo

2007

Journal of Cell Science

127

121

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Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. PARs play crucial roles in hemostasis and thrombosis, as well as in inflammation and vascular development. Coagulant proteases, which are generated at sites of vascular injury, act mainly through PARs to elicit signalling in a variety of cell types. Since PARs are irreversibly activated signalling must be tightly regulated. Desensitization and trafficking of proteolytically activated PARs control the magnitude, duration and spatial aspects of receptor signalling. Recent studies have revealed novel endocytic sorting mechanisms that regulate PAR signalling. PARs have also been implicated in tumor progression. PARs are overexpressed in several types of malignant cancer, transmit signals in response to tumor-generated proteases and promote tumor growth, invasion and metastasis. Recent work also indicates that matrix metalloprotease 1 (MMP-1) signals through PAR1 to promote tumor growth and invasion. In addition to PAR overexpression, tumor cells display aberrant PAR1 trafficking, which causes persistent signalling and cellular invasion. Thus, a novel type of gain-of-function in GPCR signalling in cancer can be acquired through dysregulation of receptor trafficking.

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“…Moreover, a series of cancer cell lines, including colorectal cancer cells (68), produce isoforms of pancreatic trypsinogen (mainly trypsinogens I and II). Caco-2 cells and other colon cell lines secrete trypsinogen at low concentrations into the culture medium (69). As extrapancreatic trypsinogen has been implicated in proliferation and migration (70), it will be interesting to investigate whether one of these proteases is capable of meprin-␣ activation in colorectal cancer.…”

Section: Figmentioning

confidence: 99%

Activation of Human Meprin-α in a Cell Culture Model of Colorectal Cancer Is Triggered by the Plasminogen-activating System

Rösmann

Hahn

Lottaz

et al. 2002

Journal of Biological Chemistry

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The activation of latent proenzymes is an important mechanism for the regulation of localized proteolytic activity. Human meprin-␣, an astacin-like zinc metalloprotease expressed in normal colon epithelial cells, is secreted as a zymogen into the intestinal lumen. Here, meprin is activated after propeptide cleavage by trypsin. In contrast, colorectal cancer cells secrete meprin-␣ in a non-polarized way, leading to accumulation and increased activity of meprin-␣ in the tumor stroma. We have analyzed the activation mechanism of promeprin-␣ in colorectal cancer using a co-culture model of the intestinal mucosa composed of colorectal adenocarcinoma cells (Caco-2) cultivated on filter supports and intestinal fibroblasts grown in the companion dish. We provide evidence that meprin-␣ is activated by plasmin and show that the presence of plasminogen in the basolateral compartment of the co-cultures is sufficient for promeprin-␣ activation. Analysis of the plasminogenactivating system in the co-cultures revealed that plasminogen activators produced and secreted by fibroblasts converted plasminogen to active plasmin, which in turn generated active meprin-␣. This activation mechanism offers an explanation for the observed meprin-␣ activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer.

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Trypsin is produced by and activates protease-activated receptor-2 in human cancer colon cells

Cited by 43 publications

References 0 publications

Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer

Activation of Human Meprin-α in a Cell Culture Model of Colorectal Cancer Is Triggered by the Plasminogen-activating System

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