Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Abstract

There has been recent interest in the relationship between 18 F-FDG uptake and the angiogenic activity of endothelial cells (ECs). The angiogenic process is strongly dependent on the interaction of ECs with matrix fibronectin (FN), a key regulator of EC survival, migration, and proliferation. Therefore, we investigated how FN influences EC glucose uptake and elucidated the signaling pathways that mediate this effect. Methods: Human umbilical vein ECs were allowed to adhere to FN-coated plates and were compared with control cells for 18 F-FDG uptake, membrane GLUT1 levels, and hexokinase activity. The roles of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), and Akt were evaluated with Western blotting, small interfering RNA (siRNA), and specific inhibitors. Results: FN adhesion significantly enhanced the protein-corrected 18 F-FDG uptake in HUVEC, to 2.1-, 2.7-, and 4.3-fold that in control cells by 2, 3, and 5 d, respectively. This effect was mediated by the upregulation of both membrane GLUT1 expression and hexokinase activity and was accompanied by FAK activation. Silencing of FAK signaling by siRNA completely abrogated both FN-induced FAK phosphorylation and 18 F-FDG uptake. FN also activated PI3K and Akt, well-known angiogenesis mediators, and the inhibition of either pathway totally abolished the effect of FN on 18 F-FDG uptake. Nitric oxide, a downstream Akt effector that stimulates glucose uptake, was not involved in the metabolic effect of FN. Conclusion: The results of this study demonstrated that an EC-FN interaction induces strong enhancement of 18 F-FDG uptake through the upregulation of GLUT1 expression and hexokinase activity. The findings also showed that the response occurs through FAK-mediated activation of PI3K and Akt, indicating a role for this pathway in modulating EC glucose metabolism.

Recurrent prognostic factors and expression of GLUT-1, PI3K and p-Akt in adenoid cystic carcinomas of the head and neck: Clinicopathological features and biomarkers of adenoid cystic carcinoma

“…The PI3K/Akt pathway has been shown to promote both GLUT-1 cell-surface trafficking and activity (14,15). The activation and phosphorylation of PI3K/Akt are not only well-recognized regulators of cell growth, survival and angiogenesis, but they also play an important role in promoting glucose metabolism (28). The activation of Akt may be responsible for the metabolic processes occurring during the Warburg effect (29).…”

Neuron-Derived Neurotrophic Factor Ameliorates Adverse Cardiac Remodeling After Experimental Myocardial Infarction

“…Because focal adhesion kinase (FAK) functions upstream of Akt signaling in several types of cells, including cardiac cells, [17][18][19][20] we investigated the possible participation of FAK in NDNF-induced signaling in cardiac myocytes. Treatment of NRVMs with NDNF protein led to enhanced phosphorylation of FAK at Tyr-397 ( Figure 4A).…”

iTRAQ-coupled 2D LC/MS-MS analysis of CXCR7-transfected papillary thyroid carcinoma cells: A new insight into CXCR7 regulation of papillary thyroid carcinoma progression and identification of potential biomarkers

“…TAGLN2 is a member of the calponin family of actin-binding proteins and is upregulated in lung cancer, colorectal cancer, and head and neck squamous cell carcinoma (16,45,46). Knockdown of TAGLN2 has been reported to inhibit tumor cell invasion and promote apoptosis (47,48).…”