Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 711-718
Glucocorticoids promote the proliferation and antagonize the
retinoic acid-mediated growth suppression of Epstein-Barr
virus-immortalized B lymphocytes
Michele Quaia,
Paola Zancai,
Roberta Cariati,
Silvana Rizzo,
Mauro Boiocchi, and
Riccardo Dolcetti
From the Division of Experimental Oncology 1, Centro di
Riferimento Oncologico, Aviano, Italy.
Glucocorticoids are able to release Epstein-Barr virus-immortalized
(EBV-immortalized) lymphoblastoid B cell lines (LCLs) from the
persistent growth arrest induced in these cells by retinoic acid (RA).
Moreover, physiologic concentrations of glucocorticoids efficiently
antagonized LCL growth inhibition induced by 13-cis-RA; 9-cis-RA; all-trans-RA; and Ro 40-6055, an RA 
receptor (RAR) selective agonist. RAR expression levels, however,
were not affected by glucocorticoids. Glucocorticoids, but not other
steroid hormones, directly promote LCL proliferation, a phenomenon that
was mainly mediated by down-regulation of the
cyclin-dependent kinase (CDK) inhibitor
p27Kip-1. Moreover, glucocorticoids contrasted the
up-regulation of p27Kip-1, which was underlying the
RA-induced LCL growth arrest, thereby indicating that glucocorticoids
and RA signalings probably converge on p27Kip-1. Both
antagonism of RA-mediated growth inhibition and promotion of LCL
proliferation were efficiently reversed by the glucocorticoid receptor
(GR) antagonist RU486, indicating that all of these effects were
mediated by GR. Of note, RU486 also proved to be effective in vivo and,
in mice, was able to significantly inhibit the growth of untreated LCLs
as well as LCLs growth-arrested by RA in vitro. These findings provide
a rational background to further evaluate the possible role of
glucocorticoids in the pathogenesis of EBV-related lymphoproliferations
of immunosuppressed patients. Moreover, GR antagonists deserve further
consideration for their possible efficacy in the management of these
disorders, and the use of schedules, including both RA and a GR
antagonist, may allow a more thorough evaluation of the therapeutic
potential of RA in this setting.
