Integrins as Therapeutic Targets: Successes and Cancers

Raab-Westphal, Sabine; Marshall, John F.; S, Goodman

doi:10.3390/cancers9090110

Cited by 182 publications

(183 citation statements)

References 220 publications

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“…For many years, BSP and αvβ3 integrin were considered to be attractive drug targets. Although BSP Abs and integrin antagonists seem helpful in mouse or rat models, none have been successful in clinical experiments until now. However, antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as a potential way forward .…”

Section: Discussionmentioning

confidence: 99%

Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

Wang

Song²,

Li³

et al. 2019

Cancer Science

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The underlying mechanisms of breast cancer cells metastasizing to distant sites are complex and multifactorial. Bone sialoprotein (BSP) and αvβ3 integrin were reported to promote the metastatic progress of breast cancer cells, particularly metastasis to bone. Most theories presume that BSP promotes breast cancer metastasis by binding to αvβ3 integrin. Interestingly, we found the αvβ3 integrin decreased in BSP silenced cells (BSPi), which have weak ability to form bone metastases. However, the relevance of their expression in primary tumor and the way they participate in metastasis are not clear. In this study, we evaluated the relationship between BSP, αvβ3 integrin levels, and the bone metastatic ability of breast cancer cells in patient tissues, and the data indicated that the αvβ3 integrin level is closely correlated to BSP level and metastatic potential. Overexpression of αvβ3 integrin in cancer cells could reverse the effect of BSPi in vitro and promote bone metastasis in a mouse model, whereas knockdown of αvβ3 integrin have effects just like BSPi. Moreover, The Cancer Genome Atlas data and RT‐PCR analysis have also shown that SPP1, KCNK2, and PTK2B might be involved in this process. Thus, we propose that αvβ3 integrin is one of the downstream factors regulated by BSP in the breast cancer‐bone metastatic cascade.

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Section: Discussionmentioning

confidence: 99%

Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

Wang

Song²,

Li³

et al. 2019

Cancer Science

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“…Among these miRNAs, miR‐144 was found to be significantly downregulated in cervical cancer tissues, and ectopic expression of miR‐144 could inhibit cervical cancer cell migration and invasion by targeting vascular endothelial growth factor A (VEGFA) and VEGFC (Tao et al., ). Integrin α6 (ITGA6) is a vital transmembrane protein and acts as an oncogene in various cancers (Raab‐Westphal, Marshall, & Goodman, ). ITGA6 was dramatically increased in cervical cancer tissues, and ITGA6 overexpression was demonstrated to promote tumour cell proliferation and invasion (Yang et al., ).…”

Section: Introductionmentioning

confidence: 99%

Long non‐coding RNA activated by transforming growth factor‐β promotes proliferation and invasion of cervical cancer cells by regulating the miR‐144/ITGA6 axis

Zhu

Yang

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?This study was designed to investigate the molecular mechanism and biological roles of long non‐coding RNA activated by transforming growth factor‐β (lncRNA ATB) in the progression of cervical cancer. What is the main finding and its importance?Our study provided new insight into the cross‐talk between lncRNA ATB, miR‐144 and ITGA6, shedding light on the therapy for cervical cancer. Abstract The present study was designed to investigate the molecular mechanism and biological roles of long non‐coding RNA activated by transforming growth factor‐β (lncRNA ATB) in the progression of cervical cancer. The expression levels of lncRNA ATB, miR‐144 and integrin α6 (ITGA6) were detected in human cervical cancer cell lines using quantitative real‐time PCR and western blotting. Cell viability was quantified by MTT assay at 12, 24, 36, 48 and 72 h after transfection, and cell invasion was determined by the Transwell migration assay. The association among lncRNA ATB, miR‐144 and ITGA6 was disclosed by a dual‐luciferase reporter assay. We found that lncRNA ATB was highly expressed in human cervical cancer cell lines. Further investigation indicated that lncRNA ATB functioned as a competitive endogenous RNA (ceRNA) for miR‐144 to promote cervical cancer cell proliferation and invasion. We demonstrated that ITGA6 was a direct target of miR‐144, and lncRNA ATB facilitated the proliferation and invasion of cervical cancer cells via the miR‐144/ITGA5 axis. In conclusion, the lncRNA ATB/miR‐144/ITGA6 axis might be a promising therapeutic target for cervical cancer.

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“…Heterodimeric α/β integrins comprise a large family of divalent cation-dependent adhesion receptors that mediate cell-cell and cell-matrix interactions, which underlie their essential roles in normal metazoan physiology but also in contributing to many diseases including pathologic thrombosis, inflammation, autoimmunity, osteoporosis and cancer (Raab-Westphal et al, 2017). In response to cell-activating stimuli, intracellular signals are generated that rapidly convert integrins into a ligand-binding state, a process termed inside-out activation .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Agthoven

Shams²,

Cochran

et al. 2019

Preprint

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Integrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

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Integrins as Therapeutic Targets: Successes and Cancers

Cited by 182 publications

References 220 publications

Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

Long non‐coding RNA activated by transforming growth factor‐β promotes proliferation and invasion of cervical cancer cells by regulating the miR‐144/ITGA6 axis

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

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