| Abstract: |
The retinoids are reported to chemoprevent second aerodigestive tract cancers in patients with prior lung or head and neck cancers. Since those retinoids already examined in clinical trials do not induce major clinical responses in lung cancers, it is hypothesized that the beneficial chemoprevention activity in lung neoplasias occurs within 'fields' of carcinogen-transformed epithelial cells. To begin to investigate this retinoid action during lung carcinogenesis, the BZR-T33 ras transformed human bronchial epithelial cell line that grows in an anchorage independent manner was examined. This study reports, as compared to controls, that all-trans-retinoic acid (RA)-treatment suppresses BZR-T33 proliferation in monolayer cultures and in anchorage independent and cloning efficiency growth assays. RA induces RAR-γ2 > RARγ1 in BZR-T33 cells but expression at the total cellular RNA level of RARα and RXRα is not augmented by RA-treatment. RARβ mRNA expression is repressed before and after RA-treatment and is only detected using a reverse transcription polymerase chain reaction (RT-PCR) assay. To determine directly which of these expressed retinoid receptors signals growth suppression, each receptor was individually transfected into BZR-T33 cells using episomal expression vectors. Growth inhibitory effects of these transfectants were compared to a control episomal vector in colony efficiency assays. RARγ over-expression in the presence or absence of RA-treatment did not suppress BZR-T33 growth more than controls. In contrast, over-expression of the other examined retinoid receptors inhibited BZR-T33 cellular cloning efficiency prior to RA-treatment and in this decreasing order after RA-treatment: RARα > RARβ > RXRα. The findings reported here reveal that RA suppresses proliferation and cloning efficiency in this transformed human bronchial epithelial cell through specific retinoid receptors. Further work is needed to evaluate the role of RA or its nuclear receptors in inhibiting even earlier steps in lung carcinogenesis. |
