SAICAR Stimulates Pyruvate Kinase Isoform M2 and Promotes Cancer Cell Survival in Glucose-Limited Conditions

TLDR

Pyruvate kinase M2 (PKM2) is essential for cancer cell growth and metabolic reprogramming under stress conditions. We show that the purine intermediate SAICAR accumulates during glucose starvation, allosterically activates PKM2, enhances energy metabolism and lactate production, and promotes survival of cancer cells—an effect absent in normal cells—providing a mechanism for tumor adaptation to nutrient limitation.

Abstract

Pyruvate kinase isoform M2 (PKM2) plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions. Here, we report that SAICAR (succinylaminoimidazolecarboxamide ribose-5'-phosphate, an intermediate of the de novo purine nucleotide synthesis pathway) specifically stimulates PKM2. Upon glucose starvation, cellular SAICAR concentration increased in an oscillatory manner and stimulated PKM2 activity in cancer cells. Changes in SAICAR amounts in cancer cells altered cellular energy level, glucose uptake, and lactate production. The SAICAR-PKM2 interaction also promoted cancer cell survival in glucose-limited conditions. SAICAR accumulation was not observed in normal adult epithelial cells or lung fibroblasts, regardless of glucose conditions. This allosteric regulation may explain how cancer cells coordinate different metabolic pathways to optimize their growth in the nutrient-limited conditions commonly observed in the tumor microenvironment.