The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the central role of PI3K signaling in a large array of diverse biologic processes raises concerns about its use in therapeutics and increases the need to develop sophisticated strategies for its use. In this review, we will discuss how PI3K signaling affects the growth and survival of tumor cells. From this vantage, we will consider how inhibitors of the PI3K signaling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer.
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism.
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