All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-kappa B, activated protein-1 and apoptosis in human lung cancer cells

Retinoids modulate the growth and differentiation effects of TNF but the me chanism is not understood. In this study, we investigated the effect of all -tr all-trans-retinoic acid (ATRA) on the cell surface expression of TNF re ceptors and receptor-mediated signaling in various human lung cancer cell l ines. ATRA treatment of cells that express wild-type p53 (A549 and H460), o r null p53 (H1299), or mutant p53 (H596) increased the number of TNF recept ors, as determined by the specific binding of I-125-labeled TNF to these ce lls, in a dose- and time-dependent manner. Treatment with 2 mu M ATRA for 2 4 h at 37 degrees C produced the maximal increase. Scatchard analysis indic ated that the increase inducted by ATRA was due to an increase in receptor number and not to an increase in affinity. The upmodulation of TNF receptor s nas also confirmed by covalent receptor-ligand cross-linking studies. The increase in TNF receptors sensitized H596 cells to TNF-induced activation of NF-kappa B, AP-1 and apoptosis, A549 cells, however, were completely res istant to TNF-induced activation of NF-kappa B, AP-1 and apoptosis, Treatme nt of these cells with as little as 0.5 mu M ATRA was effective in converti ng TNF-resistant cells to TNF-sensitive. Overall our results indicate that ATRA induces the TNF receptors in human lung cancer cells, which sensitizes them to TNF-induced signaling leading to activation of NF-kappa B, AP-1 an d apoptosis.