Overexpression of phospho-Akt correlates with phosphorylation of EGF receptor, FKHR and BAD in nasopharyngeal carcinoma

Abstract

Abstract. The Akt pathway is one of the most common molecular alterations in various human malignancies. However, its involvement in nasopharyngeal carcinoma (NPC) tumorigenesis has not been well established. In this study, the status of Akt activation and expression of its upstream and downstream molecules was investigated in 64 NPC and 38 non-malignant nasopharyngeal tissues by immunohistochemistry. The hotspot mutations of PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were also determined in 25 of these NPC tissues. No hotspot mutations were found in any of the samples tested. Akt was activated in 27 (42.2%) and 23 (35.9%) NPCs, as indicated by p-Akt (Thr308) and p-Akt (Ser473) immunoreactivity, respectively. PTEN loss did not correlate statistically with activated Akt. However, a positive correlation was observed between activated Akt and phospho-epidermal growth factor receptor (p-EGFR), suggesting that the EGFR signaling might be one of the upstream regulators of the Akt pathway. The phosphorylation of forkhead (FKHR) and Bcl-2 associated death domain (BAD), but not mamalian target of rapamycin and glycogen synthase kinase-3ß, was significantly correlated with Akt activation. This implies that Akt promotes cell proliferation (as estimated by and survival, at least, through the inactivation of FKHR and BAD in NPC. Our data revealed that the EGFR/PI3K/Akt signaling pathway is important in NPC pathogenesis and that PIK3CA hotspot mutations are rare in NPC.

Hotspot mutations in common oncogenes are infrequent in nasopharyngeal carcinoma

“…This mutant was previously reported by Chou et al in 4 NPC patients (17). Moreover, in comparison with the mutation rate of 7.6% (8/105) reported by COSMIC database (including cell line data), this study found a similar mutation frequency of 5.6% (8/168) in PIK3CA oncogene (Table V) (18,33,40).…”

“…Despite the fact that chromosomal abnormalities (13) together with amplification of certain oncogenes have been identified in NPC (14,15), information regarding oncogene mutations in NPC is limited (16). Several studies demonstrated that oncogene phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) mutation was an uncommon event in NPC patients (17)(18)(19). No EGFR kinase domain mutation was found in 60 Moroccan NPC patients (20).…”

Metformin Induces G1 Cell Cycle Arrest and Inhibits Cell Proliferation in Nasopharyngeal Carcinoma Cells

“…It is endemic in southern parts of China, Southeast Asia, the Mediterranean basin, and Alaska (McDermott et al, 2001). Epidemiologic investigations suggest that the etiology of NPC is associated with a complex interaction of genetic, viral, environmental, and dietary factors (Yip et al, 2008). Because of the anatomic location of nasopharyngeal tumors, they are traditionally treated by the combination of radiotherapy and adjuvant platinum-based chemotherapy, rather than surgery (Al-Sarraf et al, 1998), but the 5-year survival rate after this treatment is only about 50%-60%, and the rates of 5-year cumulative local relapse and distant metastasis are 20%-30% and 20%-25%, respectively (Dickson and Flores, 1985;Fandi et al, 1994).…”

“…However, the effects of metfomin on the NPC have not been reported. Considering that Akt is frequently activated in NPC cell lines and in NPC tissues (Morrison et al, 2004;Yip et al, 2008), and that the potential involvement of Akt/ mTORC1 signaling in NPC carcinogenesis (Ma et al, 2009), in current study we examined the effect of metformin on mTORC1 signaling, cell cycle progression, and cell proliferation in NPC cell line C666-1.…”

pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma

“…24 Tyr 1068 is a classic RTK auto-phosphorylation site and potentiates docking of growth factor receptor binding protein Grb1 to EGFR, with subsequent activation of MAPK/extracellular signal-regulated kinase and phosphoinositide-3-kinase/AKT signaling cascades, respectively. 25,26 These events lead to the autophosphorylation of multiple tyrosine residues in the COOH-terminal tail of the molecule that serve as binding sites for cytosolic signaling proteins containing Src homology 2 (SH2) domains and phosphotyrosine binding domains. Previous results demonstrated an association between c-Src and EGFR that results in the appearance of two tyrosine phosphorylations, one of which is Tyr 845.…”