© 2005 Oxford University Press
ARTICLE |
A Novel Retinoic Acid Receptor 
Isoform and Retinoid Resistance in Lung Carcinogenesis
Affiliations of authors: Department of Pharmacology and Toxicology (WJP, NL, AB, RB, YM, SJF, ED), Department of Medicine (WJP, KHD, ED), Norris Cotton Cancer Center (KHD, ED), Dartmouth College (CN), Hanover, NH
Correspondence to: W. Jeffrey Petty, MD, Internal Medicine—Hematology and Oncology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 (e-mail: wpetty{at}wfubmc.edu).
Background: We previously reported that all-trans-retinoic acid (RA) treatment can prevent in vitro transformation of immortalized human bronchial epithelial (HBE) cells. Methods: To determine whether methylation inhibits RAR
expression in HBE cells, we used sodium bisulfite sequencing to compare RAR P2 promoter methylation patterns in RA-sensitive (BEAS-2B) and RA-resistant (BEAS-2B-R1) HBE cells. Immunoblotting was used to assess induction of the RAR, placental transforming growth factor (PTGF-), Fos-related antigen 1 (Fra-1), and transglutaminase II (TGase II) proteins by RA following treatment with azacitidine, a DNA demethylating agent. The expression, transcriptional activity, and growth suppressive activity of RAR1', a novel RAR isoform, were evaluated in lung cancer cells transfected with RAR1', and expression was also studied in paired normal lung tissues and lung tumors. All statistical tests were two-sided. Results: Hypermethylation was observed in the 3' region of the RAR P2 promoter of BEAS-2B-R1 but not BEAS-2B cells. Azacitidine treatment of BEAS-2B-R1 cells restored RA-inducible RAR2 and PTGF- expression but not that of RAR1', Fra-1, or TGase II. RAR1' expression was repressed in RA-resistant BEAS-2B-R1 cells and in lung cancers, compared with adjacent normal lung tissues. BEAS-2B-R1 cells transiently transfected with RAR1' had increased RA-dependent activation of a retinoic acid receptor element (RARE)–containing reporter plasmid compared with vector control (mean = 3.2, 95% confidence interval [CI] = 3.1 to 3.3 versus mean = 1.4, 95% CI = 1.3 to 1.5; P<.001). In H358 lung cancer cells transiently transfected with RAR1', RA treatment restored target gene expression compared with that in vector-transfected cells and suppressed cell growth compared with that in untreated cells (4 µM; treated mean = 0.49 versus untreated mean = 1.0, difference = 0.51, 95% CI = 0.35 to 0.67, P = .003; 8 µM: treated mean = 0.50 versus untreated mean = 1.0, difference = 0.50, 95% CI = 0.26 to 0.74, P = .015). Conclusion: Restoration of RAR1' expression may overcome retinoid resistance in lung carcinogenesis.
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RAR1': Primed To Fight Retinoid Resistance in Lung Carcinogenesis
- Anita L. Sabichi, Xiaochun Xu, and Scott M. Lippman
J Natl Cancer Inst 2005 97: 1632-1633.[Extract] [Full Text] [PDF]
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