Differential response to 1α, 25-dihydroxyvitamin D3 (1α,25(OH)2D3) in non-small cell lung cancer cells with distinct oncogene mutations1
We previously demonstrated that non-small cell lung cancer (NSCLC) cells and primary human lung tumors aberrantly express the vitamin D 3 -catabolizing enzyme, CYP24, and that CYP24 restricts transcriptional regulation and growth control by 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) in NSCLC cells...
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Veröffentlicht in: | The Journal of steroid biochemistry and molecular biology 2012-09, Vol.136, p.264-270 |
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Sprache: | eng |
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Zusammenfassung: | We previously demonstrated that non-small cell lung cancer (NSCLC) cells and primary human lung tumors aberrantly express the vitamin D
3
-catabolizing enzyme, CYP24, and that CYP24 restricts transcriptional regulation and growth control by 1α,25-dihydroxyvitamin D
3
(1,25(OH)
2
D
3
) in NSCLC cells. To ascertain the basis for CYP24 dysregulation, we assembled a panel of cell lines that represent distinct molecular classes of lung cancer: Cell lines were selected which harbored mutually exclusive mutations in either the
K-ras
or the
Epidermal Growth Factor Receptor
(EGFR) genes. We observed that
K-ras
mutant lines displayed a basal vitamin D receptor (VDR)
low
CYP24
high
phenotype, whereas
EGFR
mutant lines had a VDR
high
CYP24
low
phenotype. A mutation-associated difference in
CYP24
expression was also observed in clinical specimens. Specifically,
K-ras
mutation was associated with a median 4.2-fold increase in
CYP24
mRNA expression (p = 4.8 × 10
−7
) compared to
EGFR
mutation in a series of 147 primary lung adenocarcinoma cases. Because of their differential basal expression of VDR and CYP24, we hypothesized that NSCLC cells with an
EGFR
mutation would be more responsive to 1,25(OH)
2
D
3
treatment than those with a
K-ras
mutation. To test this, we measured the ability of 1,25(OH)
2
D
3
to increase reporter gene activity, induce transcription of endogenous target genes, and suppress colony formation. In each assay, the extent of 1,25(OH)
2
D
3
response was greater in
EGFR
mutation-positive HCC827 and H1975 cells than in
K-ras
mutation-positive A549 and 128.88T cells. We subsequently examined the effect of combining 1,25(OH)
2
D
3
with erlotinib, which is used clinically in the treatment of
EGFR
mutation-positive NSCLC. 1,25(OH)
2
D
3
/erlotinib combination resulted in significantly greater growth inhibition than either single agent in both the erlotinib-sensitive HCC827 cell line and the erlotinib-resistant H1975 cell line. These data are the first to suggest that
EGFR
mutations may identify a lung cancer subset which remains responsive to and is likely to benefit from 1,25(OH)
2
D
3
administration. |
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ISSN: | 0960-0760 1879-1220 |
DOI: | 10.1016/j.jsbmb.2012.09.022 |