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Evidence for the Involvement of Both Retinoic Acid Receptor- and
Retinoic X Receptor-Dependent Signaling Pathways in the Induction of
Tissue Transglutaminase and Apoptosis in the Human Myeloma Cell Line
RPMI 8226
Bertrand Joseph,
Olga Lefebvre,
Claude Méreau-Richard,
Pierre-Marie Danzé,
Marie-Thérèse Belin-Plancot, and
Pierre Formstecher
From the INSERM U459 «Signaux, Récepteurs et
Différenciation Cellulaire», Faculté de Médecine,
Lille cedex, France.
In this study, we show that both all-trans-retinoic acid
(atRA) and 9-cis-retinoic acid (9-cis-RA) are
potent inducers of tissue transglutaminase (TGase II), an enzyme
involved in apoptosis, at the level of both enzyme activity and mRNA in
the human myeloma cell line RPMI 8226. RPMI 8226 cells were shown to
express mRNAs for all the retinoid receptors subtypes, ie,
RAR , RAR , RAR , RXR, RXR, and RXR. To
identify which of these receptors are involved in regulating TGase II
expression, several receptor-selective synthetic retinoids were used.
Neither CD367, a very potent retinoid that selectively binds and
activates receptors of the RAR family, nor CD2425, an RXR-selective
agonist, induced TGase II when used alone. However, combination of
CD367 and CD2425 resulted in nearly full induction of the enzyme.
Moreover, when used in combination with atRA, CD367 partially
inhibited the atRA-dependent induction of TGase II, whereas
CD2425 enhanced it. The effects of Am 580, CD417, and CD437, three
synthetic retinoids selective for the RARs subtypes RAR, RAR, and
RAR, respectively, were also investigated. None of these compounds
was able to induce TGase II when used alone; however, the combination
of each of them with CD2425 resulted in strong induction of the enzyme
activity, reaching 30% to 50% of the values obtained in the presence
of retinoic acid and suggesting functional redundancy between the RAR
subtypes. Finally, treatment with atRA or the combination of
CD367 and CD2425, but not with CD367 or CD2425 alone, was also shown to
trigger apoptosis in RPMI 8226 cells, with prominent accumulation of
TGase II immunoreactivity in apoptotic cells. Taken together these data
suggest that the induction of TGase II expression and apoptosis in the
RPMI 8226 myeloma cell line required ligand-dependent activation of
both the RAR and RXR receptors.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2423-2432
© 1998 by The American Society of Hematology.
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