Regulation of RAR beta expression by RAR- and RXR-selective retinoids in human lung cancer cell lines: effect on growth inhibition and apoptosis induction.
Retinoids regulate the growth and differentiation of human tracheobronchial epithelial cells. In this study, we investigated the effects of all-trans-retinoic acid (trans-RA) and receptor class-selective retinoids on the growth and apoptosis of human lung cancer cell lines. Trans-RA significantly inhibited the growth of Calu-6 and H460 cells, accompanied by induction of RA receptor (RAR) beta expression. In contrast, it had little effect on the growth of H292, SK-MES-1 and H661 lung cancer cell lines, in which RAR beta expression was not induced. Stable expression of RAR beta in RAR beta-negative, trans-RA-resistant SK-MES-1 and H661 lung cancer cells led to recovery of trans-RA-induced growth inhibition, which occurred, however, only at low serum concentration. Using fluorescent microscopy and the terminal deoxyribonucleotidyl transferase (TdT) assay, we demonstrated that induction of apoptosis by trans-RA contributed to its growth-inhibitory effect in trans-RA-sensitive lung cancer cell lines. Analysis of RAR-selective and retinoid X receptor (RXR)-selective retionoids showed that activation of both RARs and RXRs could induce growth inhibition in trans-RA-sensitive lung cancer cells. Also, an additive synergistic effect on growth inhibition and RAR beta induction was observed when cells were treated with combinations of RAR-selective and RXR-selective retinoids. Together, our results show that expression of RAR beta plays a role in mediating retinoid response in lung cancer cells and that activation of RARs or RXRs contributes to induction of RAR beta, growth inhibition and apoptosis by retinoids.
Li
Y
Y
Burnham Institute, La Jolla Cancer Research Center, CA 92037, USA.
Dawson
M I
MI
Agadir
A
A
Lee
M O
MO
Jong
L
L
Hobbs
P D
PD
Zhang
X K
XK
D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D018168:Receptors, Retinoic Acid; D014212:Tretinoin