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

Oncogene volume 19, pages 2110–2119 (2000)Cite this article

Abstract

Retinoids modulate the growth and differentiation effects of TNF but the mechanism is not understood. In this study, we investigated the effect of all-trans-retinoic acid (ATRA) on the cell surface expression of TNF receptors and receptor-mediated signaling in various human lung cancer cell lines. ATRA treatment of cells that express wild-type p53 (A549 and H460), or null p53 (H1299), or mutant p53 (H596) increased the number of TNF receptors, as determined by the specific binding of 125I-labeled TNF to these cells, in a dose- and time-dependent manner. Treatment with 2 μM ATRA for 24 h at 37°C produced the maximal increase. Scatchard analysis indicated that the increase induced by ATRA was due to an increase in receptor number and not to an increase in affinity. The upmodulation of TNF receptors was also confirmed by covalent receptor-ligand cross-linking studies. The increase in TNF receptors sensitized H596 cells to TNF-induced activation of NF-κB, AP-1 and apoptosis. A549 cells, however, were completely resistant to TNF-induced activation of NF-κB, AP-1 and apoptosis. Treatment of these cells with as little as 0.5 μM ATRA was effective in converting 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-κB, AP-1 and apoptosis.

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Abbreviations

TNF:

tumor necrosis factor

ATRA:

all-trans retinoic acid

NSCLC:

non-small cell lung cancer cells

FBS:

fetal bovine serum

AMF:

autocrine motility factor

MTS:

(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt

IL:

interleukin

TGF:

transforming growth factor

DSS:

Disuccinimidyl suberate

BSA:

bovine serum albumin

PBS:

phosphate-buffered saline

EGF:

epidermal growth factor

NGF:

nerve growth factor

PkC:

protein kinase C

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Acknowledgements

We wish to thank Dr Kapil Mehta for critical reading of the manuscript and Mr Walter Pagel for editorial suggestions. This research was conducted, in part, with a support from The Clayton Foundation of Research.

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  1. Department of Bioimmunotherapy, Cytokine Research Laboratory, Box 143, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Sunil K Manna & Bharat B Aggarwal

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  1. Sunil K Manna
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  2. Bharat B Aggarwal
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Manna, S., Aggarwal, B. All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-κB, activated protein-1 and apoptosis in human lung cancer cells. Oncogene 19, 2110–2119 (2000). https://doi.org/10.1038/sj.onc.1203547

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