Open AccessRetinoic acid modulates the in vivo and in vitro growth of IL‐6 autocrine human myeloma cell lines via induction of apoptosis
Author(s) -
LEVY Y.,
LABAUME S.,
COLOMBEL M.,
BROUET J. C.
Publication year - 1996
Publication title -
clinical & experimental immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 135
eISSN - 1365-2249
pISSN - 0009-9104
DOI - 10.1046/j.1365-2249.1996.d01-637.x
Subject(s) - autocrine signalling , in vivo , cell culture , retinoic acid , biology , apoptosis , cell growth , in vitro , cancer research , microbiology and biotechnology , immunology , biochemistry , genetics
We previously showed that IL‐6 is an autocrine growth factor for two human myeloma cell lines, RPMI 8226 and U266. We investigated here the in vitro and in vivo effects of all‐trans retinoic acid (RA) on the growth and survival of these two cell lines. RA induced a dramatic dose‐ and time‐dependent inhibition of the proliferation of both cell lines. This inhibition was correlated with a down‐modulation of the cell surface expression of the IL‐6 binding chain (gp80) and the transducing chain (gp130) of the IL‐6 receptor (IL‐6R). Long‐term culture experiments showed that down‐modulation of gp80 expression was complete at days 15 and 30 in the presence of 10 –5 and 10 –7 mol/ l of RA, respectively. Gp130 expression was greatly decreased, albeit still detectable, in similar culture conditions. RA‐mediated interruption of the IL‐6 autocrine loop was associated with a decrease of bcl‐2 oncoprotein expression and apoptosis of the myeloma cells which was RA concentration‐ and time‐dependent. The in vivo relevance of the effects of RA was studied on tumours which developed in nude mice inoculated with a subclone of RPMI 8226. Whereas tumours grew in all control mice, 40% of tumours regressed within 20 days in RA‐treated mice. Cells from regressing tumours featured characteristics of apoptosis and exhibited low gp80 and gp 130 expression. Our study indicate that long‐term RA treatment interferes in vivo and in vitro with IL‐6 autocrine growth of myeloma cell lines, leading to apoptosis.