Plk1 Coordinates Biosynthesis During Cell Cycle Progression By Directly Activating PPP Pathway

Malignant tumor is one of the most challenging diseases facing to all human beings.With the deepening research of cancer,scientists have discovered and summarized ten hallmarks of cancer.Among them,two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism.Currently,the regulatory mechanism of cancer cell cycle is becoming clearer and clearer.Aberrant expression and mutation of cell cycle related proteins facilitate cell cycle to break the restraint of checkpoints.Cell metabolism is becoming the central issue of cancer research,which functions as the support of tumor life activity.Targeting the aberrant metabolism of cancer,which is recognized as the Achilles’ heel is to be used in clinical therapy.However,how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood.Here,we identify that Polo-like kinase 1(Plk1),a key regulator that is essential for mitosis and cell cycle progression,plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway(PPP).We find that Plkl interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase(G6PD),a rate-limiting enzyme of PPP.By activating G6PD through promoting the formation of its active dimer,Plk1 increases PPP flux and directs glucose to the production of NADPH and ribose for the synthesis of macromolecules.Importantly,we further demonstrate that Plkl-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth both in vitro and in vivo.Collectively,these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells,exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression.Our study make a step further for the understanding of the crosstalk between different hallmarks of cancer,which facilitate the proliferation of cancer,and providing a novel strategy for combinational therapy of cancer.