SAICAR acts as a master metabolite in cancer cell growth, survival, and proliferation

cancer;cancer metabolism;purine nucleotides;PKM2;SAICAR;protein-ligand interactions;Biology

Keller, Kirstie E.Wendland, Beverly R. ;

Johns Hopkins University

关键词: cancer;    cancer metabolism;    purine nucleotides;    PKM2;    SAICAR;    protein-ligand interactions;    Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40190/KELLER-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Cancer cells must reprogram their metabolic networks to adapt to stress conditions, which are commonly found in a tumor microenvironment.To accomplish this, cancer cells alter expression and regulation of many target proteins.Among these, the glycolytic enzyme pyruvate kinase M2 (PKM2) has been implicated as essential for cancer cell growth and survival in stress conditions. As with other pyruvate kinases, PKM2 catalyzes the final step of glycolysis, dephosphorylating phosphoenol pyruvate (PEP) to generate pyruvate and ATP.PKM2 is differentially expressed in highly proliferating tissues including cancer cells, and has intrinsically lower activity than other pyruvate kinases. However, the role of PKM2 and its function in cancer cells remains poorly understood.In this study, we have identified a novel protein-metabolite interaction between PKM2 and the cellular metabolite succinyl-aminoimidazole carboxamide-ribosyl-5-phosphate (SAICAR) that promotes cancer cell growth.We found that SAICAR, a de novo purine nucleotide biosynthesis intermediate, accumulates in an oscillatory manner in glucose deprived cancer cells, but not in normal cells.SAICAR activates PKM2 both in vitro and in vivo, and induces metabolic reprogramming by augmenting the Warburg effect.Additionally, accumulation of SAICAR promotes long-term cancer cell survival in glucose-limited conditions, in a PKM2-dependent manner.The activation of PKM2 by SAICAR demonstrates that cancer cells coordinate a delicate balance between metabolic pathways to optimize their survival in stress conditions.Recent literature has shown that PKM2 is capable of acting as a protein kinase, and phosphorylation of its targets promotes long-term cellular adaptation.However, the mechanism and extent of this novel function is not fully understood.In this study, we also identified SAICAR as an activator of PKM2 protein kinase function.SAICAR binding renders PKM2 an efficient protein kinase both in vitro and in vivo.Additionally, we identified that PKM2-SAICAR phosphorylates over 100 cellular proteins, many of which are involved in cell proliferation and survival.Of these, we found that PKM2-SAICAR phosphorylates and activates Erk1/2, forming a positive feedback loop that is necessary for long term proliferative signaling.Taken together, our study demonstrates that cancer cells utilize the PKM2-SAICAR interaction to couple metabolic status with long-term proliferation and survival.