Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma

Kurio, Naito; Shimo, Tsuyoshi; Fukazawa, Takuya; Okui, Tatsuo; Hassan, Nur Mohammad Monsur; Honami, Tatsuki; Horikiri, Yuu; Hatakeyama, Shinji; Takaoka, Munenori; Naomoto, Yoshio; Sasaki, Akira

doi:10.1016/j.oraloncology.2012.05.019

Cited by 26 publications

(23 citation statements)

References 29 publications

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“…In contrast, we analyzed 47 clinical specimens and clearly showed the statistical significance of FAK expression or pY397 in benign, preliminary, or malignant tissues. Thus, our study provided statistical, quantitative results as compared with the work of Kurio et al 8 . Furthermore, we demonstrated the functional role of FAK and its pY397 in regulating the Rac1 activity and the migration and invasion in OSCC cells.…”

Section: Discussionmentioning

confidence: 74%

“…25 In addition, TAE226 that blocks the ATP binding site of FAK and suppresses pY397 greatly inhibits OSCC cell migration and invasion. 8 Alternatively, 1,2,4,5-benzenetetramine tetrahydrochloride (Y15), a molecule inhibiting specifically to the Y397 site without affecting ATP binding, can effectively suppress the adhesion and tumorigenesis of pancreatic cancer cells. 26 These results collectively support the notion that pY397 is required for FAK-promoted invasion in malignant cells.…”

Section: Discussionmentioning

confidence: 99%

“…5 In OSCC cells, the expression of FAK in the primary or invasive OSCC tumors is higher than that in benign oral tissues, and modulation of FAK expression or activity regulates the invasive properties of OSCC cells. [6][7][8] However, the role of Y397 phosphorylation (pY397) in the FAK-promoted invasiveness in OSCC cells and its possible mechanism is mostly unknown.…”

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confidence: 99%

“…However, in the work of Kurio et al, 8 only one cell line (SAS) was used for examining the effects of FAK inhibitor TAE226 on cell migration and invasion without further mechanism-related study. Thus, we took a step from the work of Kurio et al 8 to further demonstrate the underlying mechanism that FAK signaling via the activation of Rac1, but not cortactin, promoted OSCC cell migration and invasion.…”

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Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. Oral squamous cell carcinoma (OSCC) is the most common malignancy occurring in the oral cavity that usually arises from the buccal mucosa and tongue. During the tumor progression, OSCC cells gradually spread and invade to neighboring tissues, including the nasal cavity or the maxillary facial structures, and eventually metastasize to neck lymph nodes and distant organs. 1 Similar to other malignant diseases, tumor metastasis is a great challenge for the treatment of OSCC. This notion is supported by the fact that only 50% of diagnosed OSCC patients can survive for 5 years, and this is mainly because OSCC patients continue to die from tumor relapse at regional or distant sites. 2 Despite advances in diagnosis and therapy in past decades, the promising strategy for treating patients with metastatic OSCC is still underdeveloped, due in part to the limited understanding of the molecular events involved in invasion and metastasis of OSCC. The underlying molecular basis of OSCC metastasis deserves intensive study.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase and functionally involves the regulatory processes of multiple cellular events, including adhesion, migration, invasion, prolifer...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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“…142,144 Conversely, expression of specific ECM proteins, such as collagen I, 145 collagen XVI, 146,147 or laminin, 148 can enhance invasion. Binding of integrins to these matrix molecules triggers a signaling cascade, including integrin-linked kinase (ILK), 149 talin, 92,150 focal adhesion kinase (FAK), [151][152][153] and Src family members, 90,154 which then link to the MAP kinase and PI3 kinase pathways for stimulation of MMPs. 82,145,149,154 It is unclear why both growth factor signaling and adhesion signaling are needed for invasion-the connection between adhesion and growth factor signaling in invadopod formation is an active area of investigation.…”

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Mechanisms of Invasion in Head and Neck Cancer

Jimenez¹,

Jayakar²,

Ow³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context.-The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed.Objectives.-To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion.Data Sources.-A literature review of peer-reviewed articles in PubMed on HNSCC invasion.Conclusions.-Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.

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TAE226, a dual inhibitor of focal adhesion kinase and insulin‐like growth factor‐I receptor, is effective for Ewing sarcoma

et al. 2019

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The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

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Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma

Cited by 26 publications

References 29 publications

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Mechanisms of Invasion in Head and Neck Cancer

TAE226, a dual inhibitor of focal adhesion kinase and insulin‐like growth factor‐I receptor, is effective for Ewing sarcoma

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