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Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells.
Am J Pathol 2011; 179(5):2625-36AJ

Abstract

Serine proteinases participate in tumor growth and invasion by cleaving and activating proteinase-activated receptors (PARs). Recent studies have implicated PAR-1 and PAR-4 (activated by thrombin) and PAR-2 (activated by trypsin but not by thrombin) in human colon cancer growth. The endogenous activators of PARs in colon tumors, however, are still unknown. We hypothesize that the kallikrein-related peptidase (KLK) family member KLK14, a known tumor biomarker, is produced by colonic tumors and signals to human colon cancer cells by activating PARs. We found that i) KLK14 mRNA was present in 16 human colon cancer cell lines, ii) KLK14 protein was expressed and secreted in colon cancer cell lines, and iii) KLK14 (0.1 μmol/L) induced increases in intracellular calcium in HT29, a human colon cancer-derived cell line. KLK14-induced calcium flux was associated with internalization of KLK14-mediated activation of PAR-2. Furthermore, KLK14 induced significant extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation and HT29 cell proliferation, presumably by activating PAR-2. A PAR-2 cleavage and activation-blocking antibody dramatically reduced KLK14-induced ERK1/2 signaling. Finally, ectopic expression of KLK14 in human colon adenocarcinomas and its absence in normal epithelia was demonstrated by IHC analysis. These results demonstrate, for the first time, the aberrant expression of KLK14 in colon cancer and its involvement in PAR-2 receptor signaling. Thus, KLK14 and its receptor, PAR-2, may represent therapeutic targets for colon tumorigenesis.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale (INSERM) U773, Centre de Recherche Biomédicale Bichat-Beaujon, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21907696

Citation

Gratio, Valérie, et al. "Kallikrein-related Peptidase 14 Acts On Proteinase-activated Receptor 2 to Induce Signaling Pathway in Colon Cancer Cells." The American Journal of Pathology, vol. 179, no. 5, 2011, pp. 2625-36.
Gratio V, Loriot C, Virca GD, et al. Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. Am J Pathol. 2011;179(5):2625-36.
Gratio, V., Loriot, C., Virca, G. D., Oikonomopoulou, K., Walker, F., Diamandis, E. P., ... Darmoul, D. (2011). Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. The American Journal of Pathology, 179(5), pp. 2625-36. doi:10.1016/j.ajpath.2011.07.016.
Gratio V, et al. Kallikrein-related Peptidase 14 Acts On Proteinase-activated Receptor 2 to Induce Signaling Pathway in Colon Cancer Cells. Am J Pathol. 2011;179(5):2625-36. PubMed PMID: 21907696.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. AU - Gratio,Valérie, AU - Loriot,Céline, AU - Virca,G Duke, AU - Oikonomopoulou,Katerina, AU - Walker,Francine, AU - Diamandis,Eleftherios P, AU - Hollenberg,Morley D, AU - Darmoul,Dalila, Y1 - 2011/09/09/ PY - 2011/02/08/received PY - 2011/07/07/revised PY - 2011/07/26/accepted PY - 2011/9/13/entrez PY - 2011/9/13/pubmed PY - 2012/1/25/medline SP - 2625 EP - 36 JF - The American journal of pathology JO - Am. J. Pathol. VL - 179 IS - 5 N2 - Serine proteinases participate in tumor growth and invasion by cleaving and activating proteinase-activated receptors (PARs). Recent studies have implicated PAR-1 and PAR-4 (activated by thrombin) and PAR-2 (activated by trypsin but not by thrombin) in human colon cancer growth. The endogenous activators of PARs in colon tumors, however, are still unknown. We hypothesize that the kallikrein-related peptidase (KLK) family member KLK14, a known tumor biomarker, is produced by colonic tumors and signals to human colon cancer cells by activating PARs. We found that i) KLK14 mRNA was present in 16 human colon cancer cell lines, ii) KLK14 protein was expressed and secreted in colon cancer cell lines, and iii) KLK14 (0.1 μmol/L) induced increases in intracellular calcium in HT29, a human colon cancer-derived cell line. KLK14-induced calcium flux was associated with internalization of KLK14-mediated activation of PAR-2. Furthermore, KLK14 induced significant extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation and HT29 cell proliferation, presumably by activating PAR-2. A PAR-2 cleavage and activation-blocking antibody dramatically reduced KLK14-induced ERK1/2 signaling. Finally, ectopic expression of KLK14 in human colon adenocarcinomas and its absence in normal epithelia was demonstrated by IHC analysis. These results demonstrate, for the first time, the aberrant expression of KLK14 in colon cancer and its involvement in PAR-2 receptor signaling. Thus, KLK14 and its receptor, PAR-2, may represent therapeutic targets for colon tumorigenesis. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/21907696/Kallikrein_related_peptidase_14_acts_on_proteinase_activated_receptor_2_to_induce_signaling_pathway_in_colon_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(11)00735-8 DB - PRIME DP - Unbound Medicine ER -