Alternagin-C (ALT-C), a disintegrin-like protein, attenuates alpha2beta1 integrin and VEGF receptor 2 signaling resulting in angiogenesis inhibition

Santos, Patty Karina dos; Altei, Wanessa Fernanda; Danilucci, Taís M.; Lino, Rafael Luis Bressani; Pachane, Bianca Cruz; Nunes, Ana Carolina Caetano; Araújo, Heloísa Sobreiro Selistre de

doi:10.1016/j.biochi.2020.04.023

Cited by 21 publications

(13 citation statements)

References 59 publications

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“…VEGF can interact with integrin by VEGFR2 and activate the binding function of multiple integrins in both endothelial and tumor cells through the PI3K/AKT pathway 24 . Impairing the interaction between integrin α2β1 and VEGFR2 inhibits angiogenesis and migration of HUVEC 25 . Here, we examined whether the impaired angiogenesis may correlate with integrin and VEGF downregulation.…”

Section: Discussionmentioning

confidence: 98%

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

et al. 2020

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Glioblastoma, also known as glioblastoma multiforme (GBM), is a fast‐growing tumor and the most aggressive brain malignancy. Proteasome subunit beta type‐8 (PSMB8) is one of the 17 essential subunits for the complete assembly of the 20S proteasome complex. The aim of the present study was to evaluate the role of PSMB8 expression in GBM progression and angiogenesis. PSMB8 expression in glioblastoma LN229 and U87MG was knocked down by siRNA or inducible shRNA both in vitro and in vivo. After PSMB8 reduction, cell survival, migration, invasion, angiogenesis, and the related signaling cascades were evaluated. An orthotopic mouse tumor model was also provided to examine the angiogenesis within tumors. A GEO profile analysis indicated that high expression of PSMB8 mRNA in GBM patients was correlated with a low survival rate. In immunohistochemistry analysis, PSMB8 expression was higher in high‐grade than in low‐grade brain tumors. The proliferation, migration, and angiogenesis of human GBM cells were decreased by PSMB8 knockdown in vitro. Furthermore, phosphorylated focal adhesion kinase (p‐FAK), p‐paxillin, MMP2, MMP9, and cathepsin B were significantly reduced in LN229 cells. Integrin β1 and β3 were reduced in HUVEC after incubation with LN229‐conditioned medium. In an orthotopic mouse tumor model, inducible knockdown of PSMB8 reduced the expression of vascular endothelial growth factor (VEGF), VEGF receptor, and CD31 as well as the progression of human glioblastoma. In this article, we demonstrated the role of PSMB8 in glioblastoma progression, especially neovascularization in vitro and in vivo. These results may provide a target for the anti–angiogenic effect of PSMB8 in glioblastoma therapy in the future.

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Section: Discussionmentioning

confidence: 98%

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

et al. 2020

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“…A representative member of this subclass is the protein Alternagin isolated from the venom of Bothrops alternatus ( Souza et al, 2000 ). Alternagin inhibits α 2 β 1 integrin, thereby decreasing cell adhesion to type I collagen ( Selistre-de-Araujo et al, 2005 ) and interferes with the α 2 β 1 /VEGFR2 crosstalk, thus inhibiting angiogenesis in HUVECs ( dos Santos et al, 2020 ). Other example of the P-IIIb subclass is the protein TSV-DM purified from Trimeresurus stejnegeri venom wich potentially induces apoptosis on vascular endothelial cells ( Wan et al, 2006a ).…”

Section: Snake Venom Metalloproteinases (Svmps)mentioning

confidence: 99%

“… Albocollagenase P-IIIa Metalloproteinase, disintegrin-like and cysteine rich domains Cryptelytrops albolaris Inhibition of collagen-induced platelet aggregation, type IV collagenase Pinyachat et al (2011) 6. Alternagin-C P-IIIb Disintegrin-like domain linked to a cysteine-rich domain Bothrops alternatus Inhibition of integrin-collagen interaction, inhibition of angiogenesis in HUVECs Cominetti et al, 2004 , dos Santos et al, 2020 , Selistre-de-Araujo et al, 2005 , Souza et al, 2000 7. Catrocollastatin P-IIIb Disintegrin-like domain linked to a cysteine-rich domain Crotalus atrox Inhibition of collagen-induced platelet aggregation Fox and Serrano, 2008b , Zhou et al, 1995 8.…”

Section: Snake Venom Metalloproteinases (Svmps)mentioning

confidence: 99%

Snake Venom Metalloproteinases (SVMPs): A structure-function update

et al. 2020

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Snake venom metalloproteinases (SVMPs) represent a diverse group of multi-domain proteins with several biological activities such as the ability to induce hemorrhage, proteolytic degradation of fibrinogen and fibrin, induction of apoptosis and inhibition of platelet aggregation. Due to these activities, SVMPs are responsible for many of the well-known pathological phenotypes in snake envenomations caused particularly by species from the Viperidae family and the Crotalinae subfamily. These proteins have been classified based on their size and domain structure into P–I, P-II and P-III classes. Comparatively, members of the P–I SVMPs possess the simplest structures, formed by the catalytic metalloproteinase domain only; the P-II SVMPs are moderately more complex, having the canonical disintegrin domain in addition to the metalloproteinase domain; members of the P-III class are more structurally varied, comprising the metalloproteinase, disintegrin-like, and cysteine-rich domains. Proteolytic cleavage, repeated domain loss and presence of other ancillary domains are responsible for structural diversities in the P-III class. However, studies continue to unveil the relationship between the structure and function of these proteins. In this review, we recovered evidences from literature on the structural peculiarities and functional classification of Snake Venom Metalloproteinases. In addition, we reflect on diversities that exist among each class while taking into account specific and up-to-date class-based activities.

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“…Integrin is a cell surface receptor that mediates cell-to-cell adhesion and the cell and extracellular matrix [ 4 ]. Integrin α2 and β1 subunits form heterodimers of the transmembrane receptors, which are important molecules involved in tumor cell proliferation, migration, survival, and angiogenesis [ 5 , 6 ]. Integrin α2/β1 is overexpressed in many kinds of cancer cells, but its expression is low or even nonexistent in most normal organs and tissues [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

Cai

Guo

Wen

et al. 2022

J Exp Clin Cancer Res

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Background Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear. Methods The GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test. Results The results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway. Conclusions Taken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic cancer.

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Alternagin-C (ALT-C), a disintegrin-like protein, attenuates alpha2beta1 integrin and VEGF receptor 2 signaling resulting in angiogenesis inhibition

Cited by 21 publications

References 59 publications

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

Snake Venom Metalloproteinases (SVMPs): A structure-function update

Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

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