The role of FAK in tumor metabolism and therapy

Abstract

Focal adhesion kinase (FAK) plays a vital role in tumor cell proliferation, survival and migration. Altered metabolic pathways fuel rapid tumor growth by accelerating glucose, lipid and glutamine processing. Besides the mitogenic effects of FAK, evidence is accumulating supporting the association between hyper-activated FAK and aberrant metabolism in tumorigenesis. FAK can promote glucose consumption, lipogenesis, and glutamine dependency to promote cancer cell proliferation, motility, and survival. Clinical studies demonstrate that FAK-related alterations of tumor metabolism are associated with increased risk of developing solid tumors. Since FAK contributes to the malignant phenotype, small molecule inhibition of FAK-stimulated bioenergetic and biosynthetic processes can provide a novel approach for therapeutic intervention in tumor growth and invasion.

Keywords: Focal adhesion kinase; Glutamine; Lipogenesis; Molecular targeting; Motility; Proliferation.

Fig 1.. FAK modulation of cancer cell glucose consumption and proliferation.

Growth factors, insulin/IGF1R, and/or anchorage-activated integrin trigger FAK activation. Downstream factors, IRS and PI3K/Akt induce alteration of glycolysis and mitochondrial respiration. Excessive glucose consumption provides energy and precursors to rapidly growing cells. Inhibitors targeting FAK or FAK-IGF1R interactions can prevent malignant cell glucose consumption and growth.

Fig 2.. The roles of FAK in lipid-mediated tumor growth and invasion.

FAK interactions with receptors such as IR/IGF1R/integrin and effectors such as PI3K/Akt/ERK are associated with lipid rafts. Formation and translocation of FAK-associated lipid complexes contributes to ACLY and FASN activation, channeling TCA-processed glucose to promote lipogenesis. Excessive lipid biosynthesis can induce cell growth and lipid turnover-mediated motility. Inhibition of ACLY and FASN leads to decreased lipid biosynthesis and tumor growth/invasion.

Fig 3.. FAK activation and cancer dependency on glutamine.

FAK activation of oncogenes, K-Ras and Myc, alters the activities of glutamine synthetase and glutaminase. Increased glutamine flux provides precursors for nuclei acid and protein synthesis that are essential for cell proliferation. Furthermore, cancer cells rely on glutamine consumption to generate antioxidants, that neutralize rapid growth-accelerated ROS production, for their survival.

Fig 4.. FAK modulation of cancer cell metabolism.

Insulin/IGF1 stimulates FAK-PI3K-Akt signaling through IRS. This modulates glucose metabolism via activation of glucose transporters, glycolytic and mitochondrial enzymes. Citrate can leave the TCA cycle in mitochondria and is converted to lipids. FAK activation of ERK/Akt can promote this conversion and channel glucose to lipids for the biosynthetic needs of rapidly growing cells. Anchorage-dependent stimulation of FAK activity contributes to K-Ras/Myc signaling-related glutamine metabolism.