Palbociclib treatment alters nucleotide biosynthesis and glutamine dependency in A549 cells

• DOI: 10.1186/s12935-020-01357-x
• Publication Date: 2020-07-01T07:53:05Z
• Authors: Lindsey R. Conroy; Pawel Lorkiewicz; Liqing He; Xinmin Yin; Xiang Zhang; Shesh N. Rai; Brian F. Clem
• Keywords: Palbociclib; Glutaminase; Glutaminolysis

Abstract Background Aberrant activity of cell cycle proteins is one the key somatic events in non-small lung cancer (NSCLC) pathogenesis. In most NSCLC cases, retinoblastoma protein tumor suppressor (RB) becomes inactivated via constitutive phosphorylation by cyclin dependent kinase (CDK) 4/6, leading to uncontrolled proliferation. Palbociclib, a small molecule inhibitor CDK4/6, has shown anti-tumor vitro and vivo, with recent studies demonstrating functional role for palbociclib reprogramming cellular metabolism. While efficacy preclinical models NSCLC, metabolic consequences CDK4/6 inhibition this context are largely unknown. Methods our study, we used combination stable isotope resolved metabolomics using [U- 13 C]-glucose multiple assays, interrogate perturbations induced A549 adenocarcinoma cells. Specifically, assessed changes glycolytic activity, pentose phosphate pathway (PPP), glutamine utilization. We performed these following treatment simultaneous silencing RB1 define pRB-dependent Results Our revealed does not affect cells but decreases glucose metabolism through PPP. This part reducing 6-phosphate dehydrogenase, rate limiting enzyme Additionally, enhances glutaminolysis maintain mitochondrial respiration sensitizes glutaminase inhibitor, CB-839. Notably, effects on both PPP utilization occur an RB-dependent manner. Conclusions Together, data impact may support targeting inhibitors patients RB-proficient tumors.