Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Abstract

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.

Pharmacologic Activation of PKM2 Slows Lung Tumor Xenograft Growth

“…Previous reports showed that other classes of small-molecule PKM2 activators have little or no effect on the viability of cancer cells when grown under normal conditions (26,27). We observed similar results with SGI-9380 and SGI-10067 against a number of adherent and suspension cell lines (data not shown).…”

“…SGI-9380 bound to the allosteric site with occupancy of 2 molecules per dimer (Fig. 2), whereas other PKM2 activators that bind to the same site are reported to bind with occupancy of one molecule per dimer (27). We were unable to obtain a crystal structure of SGI-10067 bound to PKM2.…”

“…In light of such evidence, efforts have focused on the discovery and development of small-molecule PKM2 activators. There are several examples of small molecules that activate PKM2 in biochemical assays (23)(24)(25), and recent reports have shown that PKM2 activators affect cancer cell growth in vitro and tumor growth in vivo (26,27).…”

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

“…We predicted that the lipogenic subtype would preferentially use glucose for the tricarboxylic acid (TCA) cycle and lipid synthesis, whereas the glycolytic subtype would use glucose more for aerobic glycolysis, and consequently, use more glutamine for TCA anaplerosis. 13 5 ]glutamine into TCA metabolites at significantly higher levels than lines from the lipogenic subtype ( Fig. 2B; P < 0.05).…”

“…The first example of metabolic reprogramming was discovered more than 80 y ago by Otto Warburg: tumor cells can shift from oxidative to fermentative metabolism in the course of oncogenesis (1). More recently, there has been a resurgence of interest in targeting cancer metabolism (2-4) because it may not only be effective in inhibiting tumor growth, but may also provide a therapeutic window (5,6). For example, inactivation of lactate dehydrogenase-A (LDHA), an enzyme that catalyzes the final step of aerobic glycolysis, thereby reducing pyruvate to lactate, decreases tumorigenesis and induces regression of established tumors in mouse models of lung cancer driven by oncogenic KRAS or epidermal growth factor receptor (EGFR) while minimally affecting normal cell function (7).…”