GROWTH SUPPRESSION OF TRANSFORMED HUMAN BRONCHIAL EPITHELIAL-CELLS BYALL-TRANS-RETINOIC ACID OCCURS THROUGH SPECIFIC RETINOID RECEPTORS

The retinoids are reported to chemoprevent second aerodigestive tract cancers in patients with prior lung or head and neck cancers, Since th ose retinoids already examined in clinical trials do not induce major clinical responses in lung cancers, it is hypothesized that the benefi cial 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 trans formed human bronchial epithelial cell line that grows in an anchorage independent manner was examined, This study reports, as compared to c ontrols, that all-trans-retinoic acid (RA)-treatment suppresses BZR-T3 3 proliferation in monolayer cultures and in anchorage independent and cloning efficiency growth assays, RA induces RAR-gamma 2 > RAR gamma 1 in BZR-T33 cells but expression at the total cellular RNA level of R AR alpha and RXR alpha is not augmented by RA-treatment, RAR beta mRNA expression is repressed before and after RA-treatment and is only det ected using a reverse transcription polymerase chain reaction (RT-PCR) assay, To determine directly which of these expressed retinoid recept ors signals growth suppression, each receptor was individually transfe cted into BZR-T33 cells using episomal expression vectors, Growth inhi bitory effects of these transfectants were compared to a control; epis omal vector in colony efficiency assays, RAR gamma over-expression in the presence or absence of RA-treatment did not suppress BZR-T33 growt h more than controls, In contrast, over-expression of the other examin ed retinoid receptors inhibited BZR-T33 cellular cloning efficiency pr ior to RA-treatment and in this decreasing order after RA-treatment: R AR alpha > RAR beta > RXR alpha, The findings reported here reveal tha t RA suppresses proliferation and cloning efficiency in this transform ed human bronchial epithelial cell through specific retinoid receptors , Further work is needed to evaluate the role of RA or its nuclear rec eptors in inhibiting even earlier steps in lung carcinogenesis.