Abstract
Background
Aberrant activity of cell cycle proteins is one of the key somatic events in non-small cell lung cancer (NSCLC) pathogenesis. In most NSCLC cases, the retinoblastoma protein tumor suppressor (RB) becomes inactivated via constitutive phosphorylation by cyclin dependent kinase (CDK) 4/6, leading to uncontrolled cell proliferation. Palbociclib, a small molecule inhibitor of CDK4/6, has shown anti-tumor activity in vitro and in vivo, with recent studies demonstrating a functional role for palbociclib in reprogramming cellular metabolism. While palbociclib has shown efficacy in preclinical models of NSCLC, the metabolic consequences of CDK4/6 inhibition in this context are largely unknown.
Methods
In our study, we used a combination of stable isotope resolved metabolomics using [U-13C]-glucose and multiple in vitro metabolic assays, to interrogate the metabolic perturbations induced by palbociclib in A549 lung adenocarcinoma cells. Specifically, we assessed changes in glycolytic activity, the pentose phosphate pathway (PPP), and glutamine utilization. We performed these studies following palbociclib treatment with simultaneous silencing of RB1 to define the pRB-dependent changes in metabolism.
Results
Our studies revealed palbociclib does not affect glycolytic activity in A549 cells but decreases glucose metabolism through the PPP. This is in part via reducing activity of glucose 6-phosphate dehydrogenase, the rate limiting enzyme in the PPP. Additionally, palbociclib enhances glutaminolysis to maintain mitochondrial respiration and sensitizes A549 cells to the glutaminase inhibitor, CB-839. Notably, the effects of palbociclib on both the PPP and glutamine utilization occur in an RB-dependent manner.
Conclusions
Together, our data define the metabolic impact of palbociclib treatment in A549 cells and may support the targeting CDK4/6 inhibition in combination with glutaminase inhibitors in NSCLC patients with RB-proficient tumors.
Document Type
Article
Publication Date
7-1-2020
Digital Object Identifier (DOI)
https://doi.org/10.1186/s12935-020-01357-x
Funding Information
This work was supported by NIH Grants S10OD020106 (XZ) and R01CA166327 (BFC) and American Cancer Society, RSG 13-139-01-CNE (BFC).
Repository Citation
Conroy, Lindsey R.; Lorkiewicz, Pawel; He, Liqing; Yin, Xinmin; Zhang, Xiang; Rai, Shesh N.; and Clem, Brian F., "Palbociclib Treatment Alters Nucleotide Biosynthesis and Glutamine Dependency in A549 Cells" (2020). Neuroscience Faculty Publications. 67.
https://uknowledge.uky.edu/neurobio_facpub/67
Additional file 1: Figure S1
Notes/Citation Information
Published in Cancer Cell International, v. 20, article no. 280.
© The Author(s) 2020
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