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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 251-259
Growth Inhibition of a Human Myeloma Cell Line by All-trans
Retinoic Acid Is Not Mediated Through Downregulation of
Interleukin-6 Receptors but Through Upregulation of
p21WAF1
Yi-Hsiang Chen,
Donald Lavelle,
Joseph DeSimone,
Shahab Uddin,
Leonidas C. Platanias, and
Maria Hankewych
From the Department of Medicine, University of Illinois College of
Medicine and VA West Side Medical Center, Chicago, IL.
All-trans retinoic acid (ATRA) has previously been shown to
inhibit the growth of OPM-2 human myeloma cells. The growth inhibition was postulated to result from a transcriptional downregulation of
interleukin-6 receptor  (IL-6R) with IL-6R (gp130) unaffected. To formally test this hypothesis, an expression vector designed for
constitutive IL-6R expression was constructed and used for transfection of OPM-2 cells. Six stable transfectants were cloned. The
expression of IL-6R was shown by immunofluorescence with anti-IL-6R antibody and 125I-IL-6 binding. In five of
six transfectant clones, cellular IL-6R was 1.5- to 6-fold higher
than the parental cells, with the ligand binding affinity unchanged.
While ATRA reduced IL-6R expression in the parental OPM-2 cells, it
enhanced its expression in these five transfectants. The clonogenic
growth of these transfectants, however, remained strongly inhibited by
ATRA. Further analysis, comparing the parental OPM-2 cells and a
representative transfectant, clone C5, showed that IL-6 caused rapid
tyrosine phosphorylation of gp130 in both OPM-2 and C5 clones.
Pretreatment with ATRA greatly reduced IL-6-induced gp130
phosphorylation in OPM-2 cells, reflecting a reduction in cellular
IL-6R. In contrast, IL-6-induced gp130 phosphorylation was not
reduced by ATRA pretreatment in C5 cells, indicating that the expressed
IL-6R was functional. Similar to OPM-2 cells, C5 cells were
sensitive to growth inhibition by dexamethasone, which was entirely
reversed by exogenous IL-6, suggesting that the IL-6 postreceptor
signal transduction remained intact. ATRA was further shown to
upregulate p21WAF1 expression and cause dephosphorylation
of the retinoblastoma protein (pRB) in both OPM-2 and C5 cells.
Exogenous IL-6 also failed to reverse these effects of ATRA. Thus, the
growth inhibitory activity of ATRA is not mediated through cellular
IL-6R downregulation and is likely to result from a direct
upregulation of p21WAF1 and consequent dephosphorylation of pRB.
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