Involvement of Integrin-Activating Peptides Derived from Tenascin-C in Cancer Aggression and New Anticancer Strategy Using the Fibronectin-Derived Integrin-Inactivating Peptide.

Motomichi Fujita,Takuya Iyoda,Fumio Fukai,Manabu Sasada

doi:10.3390/molecules25143239

Abstract

Matricellular proteins, which exist in association with the extracellular matrix (ECM) and ECM protein molecules, harbor functional sites within their molecular structures. These functional sites are released through proteolytic cleavage by inflammatory proteinases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the peptides containing these functional sites have unique biological activities that are often not detected in the parent molecules. We previously showed that tenascin-C (TNC) and plasma fibronectin (pFN), examples of matricellular proteins, have cryptic bioactive sites that have opposite effects on cell adhesion to the ECM. A peptide containing the bioactive site of TNC, termed TNIIIA2, which is highly released at sites of inflammation and in the tumor microenvironment (TME), has the ability to potently and persistently activate β1-integrins. In the opposite manner, the peptide FNIII14 containing the bioactive site of pFN has the ability to inactivate β1-integrins. This review highlights that peptide TNIIIA2 can act as a procancer factor and peptide FNIII14 can act as an anticancer agent, based on the regulation on β1-integrin activation. Notably, the detrimental effects of TNIIIA2 can be inhibited by FNIII14. These findings open the possibility for new therapeutic strategies based on the inactivation of β1-integrin by FNIII14.

Highlights

Extracellular matrix (ECM) molecules, such as fibronectin (FN), collagen, and laminin, serve as the molecular and structural scaffold for cell adhesion and for the maintenance of tissue architecture and tissue polarity
The peptide containing the bioactive site of plasma fibronectin (pFN), termed FNIII14, has the ability to inactivate β1-integrins
The effects of pFN-derived peptide FNIII14 on cell regulation, especially its antitumor applications via the inactivation of integrins, have been reported (Table 2), and these reports have suggested some of the implications for novel therapeutic approaches targeting β1-integrin activation

Summary

Introduction

Extracellular matrix (ECM) molecules, such as fibronectin (FN), collagen, and laminin, serve as the molecular and structural scaffold for cell adhesion and for the maintenance of tissue architecture and tissue polarity. The 22-mer peptide TNIIIA2 containing its functional sites can induce the activation of integrin α5β1 through a lateral association with transmembrane heparan sulfate proteoglycan syndecan-4 (Figure 1B,C), which leads to the induction and potentiation of cell adhesion to the ECM [23]. Peptide TNIIIA2 induced the platelet-derived growth factor (PDGF)-dependent dimerization (MAPK) signaling pathway, followed by the induction of hyperproliferation and the formation of dense of PDGF receptor (PDGF-R)β via the activation of integrin α5β1 to promote the multilayered cell aggregates—that is, transformed foci in NIH3T3 cells (Figure 2) [76]. Fragments/peptides might be involved in oncogenic transformation and malignant progression

Tenascin-C

Colitis-Associated Colorectal Cancer

Findings

Conclusions