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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1419-1427
NEOPLASIA
CD40 activation induces p53-dependent vascular endothelial growth
factor secretion in human multiple myeloma cells
Yu-Tzu Tai,
Klaus Podar,
Deepak Gupta,
Boris Lin,
Gloria Young,
Masaharu Akiyama, and
Kenneth C. Anderson
From the Department of Adult Oncology, Jerome Lipper
Multiple Myeloma Center, Dana-Farber Cancer Institute, and the
Department of Medicine, Harvard Medical School, Boston, MA.
It was previously demonstrated that p53 status in human multiple
myeloma (MM) cells regulates distinct cell cycle responses to CD40
activation. In this study, the production of vascular endothelial
growth factor (VEGF) and migration in MM cells triggered by CD40
activation was examined, and the influence of p53 status in regulating
this process was determined. Two human MM cell lines that express
wild-type p53 at permissive (28°C) and mutant p53 at restrictive
(37°C) temperatures were used as a model system. CD40 activation
induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF
transcripts, respectively, under restrictive, but not permissive,
temperatures. VEGF expression is significantly induced after CD40
activation in patient MM cells expressing mutant p53. Increased VEGF
transcripts result in increased protein and secretion levels, as
evidenced by immunoblotting and enzyme-linked immunosorbent assay. In a
double-chamber transmigration assay, CD40 activation of MM cells
induced a 3-fold (RPMI 8226) and a 5-fold (SV) increase in migration
under restrictive, but not permissive, conditions. A 2- to 8-fold
induction in migration of patient MM cells expressing mutant p53 was
similarly observed. Transduction of MM cells with a luciferase reporter
under the control of a human VEGF promoter further indicated that
CD40-induced VEGF expression was mediated through a transcriptional
control mechanism. Finally, adenovirus-mediated wild-type p53
overexpression down-regulated CD40-induced VEGF expression and
transmigration in MM cells expressing mutant p53. These studies
demonstrate that CD40 induces VEGF secretion and MM cell migration,
suggesting a role for CD40 in regulating MM homing and angiogenesis.
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