Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation

Fujita, Motomichi; Sasada, Manabu; Iyoda, Takuya; Nagai, Reo; Kudo, Chikako; Yamamoto, Tetsuya; Osada, Shinji; Kodama, Hiroaki; Fukai, Fumio

doi:10.1016/j.bbrc.2020.12.050

Cited by 16 publications

(13 citation statements)

References 29 publications

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“…The 22-mer peptide containing YTITIRGV termed TNIIIA2 is capable to induce activation of integrin α5β1 and to rescue non-transformed fibroblasts from serum starvation–elicited apoptosis through activation of the AKT/Bcl-2 pathway [ 350 ]. It was also found that activation of integrin α5β1 by TNIIIA2 caused active proliferation, disseminative migration and anoikis resistance in glioblastoma cells [ 351 , 352 ]. In glioblastoma cells, TNIIIA2 was also able to stimulate PDGF production that resulted in upregulation of the tenascin-C expression in these cells.…”

Section: Degradation Of the Tumourigenic Matrixmentioning

confidence: 99%

The Functional Role of Extracellular Matrix Proteins in Cancer

Popova

Jücker

2022

Cancers

106

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The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.

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Section: Degradation Of the Tumourigenic Matrixmentioning

confidence: 99%

The Functional Role of Extracellular Matrix Proteins in Cancer

Popova

Jücker

2022

Cancers

106

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“…We previously found that the FN type III repeat A2 of TNC molecule has a cryptic site, called TNIIIA2, and TNC fragments/peptides containing this cryptic site can activate β1-integrins to strengthen cell adhesion to the ECM and sustain it for long periods of time [44,45]. Based on this unique activity, we speculate that this abnormal activation of β1-integrins may be a key event in the acquisition of aggressive properties, such as excessive survival/proliferation and disseminated migration [20,21,46]. Interestingly, TNIIIA2-induced aggressive properties can be inhibited by peptide FNIII14 through the inactivation of β1-integrins in glioblastoma cells [20].…”

Section: Perspectivesmentioning

confidence: 74%

“…Our previous study showed that peptide FNIII14 can accelerate the death of glioblastoma cells in suspension culture (i.e., anchorage-independent conditions, through activation of the caspase signaling pathway). In contrast, peptides RGD and CS-1, which antagonize integrins α5β1, αvβ3, and α4β1, showed no such an effect [21]. Thus, peptide FNIII14 exhibits anti-cancer effects that cannot be achieved with conventional integrin antagonist peptides that competitively inhibit integrin-ECM binding.…”

Section: Anti-cancer Effects Of Peptide Fniii14mentioning

confidence: 93%

“…For example, glioblastoma develop their characteristic aggressive properties, such as hyperproliferation and disseminative migration, through potent and sustained activation of β1-integrin, and peptide FNIII14 can inhibit the development of these aggressive properties [20]. In addition, peptide FNIII14 inhibits the anchorage-independent survival of glioblastoma cells and overcomes their anoikis resistance [21]. In vivo experiments using a mouse xenograft model demonstrated that peptide FNIII14 also suppresses tumor growth [20].…”

Section: Anti-cancer Effects Of Peptide Fniii14mentioning

confidence: 99%

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Biofunctional Peptide FNIII14: Therapeutic Potential

et al. 2021

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Biofunctional peptide FNIII14, which is derived from the 14th fibronectin (FN) type III-like (FN-III) repeat of FN molecule, is capable of inhibiting cell adhesion to the extracellular matrix (ECM). This functional site is usually buried within the molecular structure of FN, but can be exposed by conformational changes and proteolytic cleavage. Peptide FNIII14 can induce a conformational change in β1-integrin from the active to the inactive form, causing functional inactivation. Based on this anti-adhesive activity, peptide FNIII14 exhibits therapeutic potential for several diseases such as metabolic diseases, organ fibrosis, and malignant tumors. Peptide FNIII14 blocks integrin-mediated signaling by a mechanism entirely distinct from that of conventional antagonisitic peptides, including Arg-Gly-Asp peptides that competitively inhibit the ECM binding of integrin.

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“…Because TNC variants containing the alternatively spliced domain type III-A2 are highly expressed in malignant tumors[ 49 ], the activation of beta1-integrin induced by TNIIIA2 may be related to some forms of cancer pathogenesis. We previously found that TNIIIA2 contributes to the ability of glioblastoma to acquire aggressive properties such as excessive survival/proliferation, disseminative migration, and anoikis resistance through activation of beta1-integrin[ 50 - 52 ]. More recently, we reported that TNIIIA2 establishes inflammatory environments via the NOD-like receptor family pyrin domain-containing 3/caspase-1/IL-1beta pathway[ 53 ].…”

Section: Pathological Significance Of Elevated Tnc Expression In Malignant Tumorsmentioning

confidence: 99%

Involvement of integrin-activating peptides derived from tenascin-C in colon cancer progression

Fujita¹,

Suzuki²,

Fukai³

2021

WJGO

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Tenascin-C (TNC) is an adhesion modulatory protein present in the extracellular matrix that is highly expressed in several malignancies, including colon cancer. Although TNC is considered a negative prognostic factor for cancer patients, the substantial role of the TNC molecule in colorectal carcinogenesis and its malignant progression is poorly understood. We previously found that TNC has a cryptic functional site and that a TNC peptide containing this site, termed TNIIIA2, can potently and persistently activate beta1-integrins. In contrast, the peptide FNIII14, which contains a cryptic bioactive site within the fibronectin molecule, can inactivate beta1-integrins. This review presents the role of TNC in the development of colitis-associated colorectal cancer and in the malignant progression of colon cancer, particularly the major involvement of its cryptic functional site TNIIIA2. We propose new possible prophylactic and therapeutic strategies based on inhibition of the TNIIIA2-induced beta1-integrin activation by peptide FNIII14.

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Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation

Cited by 16 publications

References 29 publications

The Functional Role of Extracellular Matrix Proteins in Cancer

The Functional Role of Extracellular Matrix Proteins in Cancer

Biofunctional Peptide FNIII14: Therapeutic Potential

Involvement of integrin-activating peptides derived from tenascin-C in colon cancer progression

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