Glucocorticoid receptor status is a principal determinant of variability in the sensitivity of non-small-cell lung cancer cells to pemetrexed. J Thorac Oncol 2014 Apr;9(4):519-26
Date
04/17/2014Pubmed ID
24736075Pubmed Central ID
PMC4075060DOI
10.1097/JTO.0000000000000111Scopus ID
2-s2.0-84922479677 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
INTRODUCTION: Pemetrexed is an S-phase targeted drug in front-line or maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC) but methods are needed for predicting the drug response. Dexamethasone is typically administered the day before, the day of, and the day after pemetrexed. As dexamethasone strongly regulates many genes including p53 through the glucocorticoid receptor (GR), we hypothesized that dexamethasone influences tumor response to pemetrexed.
METHODS: Eight nonsquamous NSCLC cell line models with varied p53 and GRα/GRβ status were used for gene expression and cell-cycle analyses and for loss- or gain-of-function experiments.
RESULTS: In three cell lines dexamethasone profoundly, but reversibly, suppressed the fraction of S-phase cells. Dexamethasone also reversibly repressed expression of thymidylate synthase and dihydrofolate reductase, which are primary targets of pemetrexed but are also quintessential S-phase enzymes as well as the S-phase-dependent expression of thymidine kinase 1. Dexamethasone also decreased expression of the major pemetrexed transporters, the reduced folate carrier and the proton coupled folate transporter. Only cells expressing relatively high GRα showed these dexamethasone effects, regardless of p53 status. In cells expressing low GRα, the dexamethasone response was rescued by ectopic GRα. Further, depletion of p53 did not attenuate the dexamethasone effects. The presence of dexamethasone during pemetrexed treatment protected against pemetrexed cytotoxicity in only the dexamethasone responsive cells.
CONCLUSIONS: The results predict that in nonsquamous NSCLC tumors, reversible S-phase suppression by dexamethasone, possibly combined with a reduction in the drug transporters, attenuates responsiveness to pemetrexed and that GR status is a principal determinant of tumor variability of this response.
Author List
Patki M, Gadgeel S, Huang Y, McFall T, Shields AF, Matherly LH, Bepler G, Ratnam MAuthor
Thomas Mcfall PhD Assistant Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antineoplastic Combined Chemotherapy ProtocolsApoptosis
Blotting, Western
Carcinoma, Non-Small-Cell Lung
Cell Cycle
Cell Proliferation
Dexamethasone
Drug Synergism
Glutamates
Guanine
Humans
Lung Neoplasms
Pemetrexed
RNA, Messenger
Real-Time Polymerase Chain Reaction
Receptors, Glucocorticoid
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Tumor Suppressor Protein p53
