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

Abstract

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...

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma

“…FAK associates with integrins or growth factor receptors and, when activated, localizes to cell-matrix contact sites, focal adhesions [ 37 – 39 ]. OSCC cells were shown to express FAK abundantly and that FAK regulated invasive properties of OSCC [ 40 ]. Ephrin-B reverse signaling alters the subcellular localization and/or tyrosine-phosphorylation levels of other proteins, including FAK and paxillin, and is involved in cytoskeletal dynamics [ 41 ].…”

Expression of human papillomavirus oncoproteins E6 and E7 inhibits invadopodia activity but promotes cell migration in HPV‐positive head and neck squamous cell carcinoma cells

“…For example, these tumors are more rigid than surrounding normal tissues, and their stromal density correlates with tumor stage, poor prognoses, and reduced survival rates . Furthermore, molecules involved in ECM cross‐linking, mechanotransduction, and invasion also correlate with cancer risk, tumor progression, and poor survival . In addition, our work has shown that ECM rigidity mimicking tumor mechanical properties promotes invadopodia activity .…”

<p>Role of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma and Its Therapeutic Prospect</p>

“…Similarly, the high-invading cell line exhibited higher expression levels of FAK and phosphorylated-Y397 (p-Y397) compared with the low-invading one. 37 Besides, the overexpression of p-Y397, FAK Tyr-576 and FAK Tyr-925 has been recently observed in tumor zones and non-neoplastic adjacent epithelial tissue of HNSCC. 38 These results indicate that FAK and its phosphorylation form are correlated with tumor invasion and metastasis.…”

“…57 Moreover, p-Y397 plays a critical role in FAK-regulated Rac1 activation and invasiveness of OSCC cells. 37 Recent research has demonstrated that spreading of endothelial cells in head and neck cancer was altered by inhibiting mTOR, which was associated with augmented p-FAK and enhanced migratory behaviour. 75 Abundant researches have revealed that FAK is involved signaling pathways that promote cancer cell adhesion, invasion and migration.…”

“… 57 Moreover, p-Y397 plays a critical role in FAK-regulated Rac1 activation and invasiveness of OSCC cells. 37 …”