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Vol. 59, Issue 1, 135-143, January 2001
Department of Biochemistry, University of Oxford, South Parks Road,
Oxford, U.K. (A.M.R.-L.); The School of Pharmacy, University of
Manchester, Manchester, U.K. (D.X., C.M.C.); Academic Unit of Pediatric
Oncology, Christie Hospital, Manchester, U.K. (T.O.B.E.); and Institut
de Recherches Servier, Paris, France (J.A.H.)
The p53 gene in neuroblastoma tumors (NB) is rarely mutated but the
protein accumulates in the cytoplasm. Because p53 can mediate the
cytotoxic effects of chemotherapeutic agents, it is important to
determine whether accumulation of p53 in the cytoplasm impairs p53
function. Data presented here indicate that hyperactive nuclear export
of p53 suppresses etoposide-induced apoptosis but does not prevent
growth arrest. We compared p53 function in a pair of NB subclones. Our
data show etoposide induces complete trans-location of
p53 to the nucleus and activation of apoptosis in the neuroblastic NB
cell line SH-SY5Y (N-type), which expresses low levels of MDM2.
However, in Schwann cell-like SH-EP1 cells (S-type), which have up to
10-fold higher levels of MDM2, p53 accumulates in the cytoplasm and the
cells are extremely resistant to etoposide-induced apoptosis. Notably,
when MDM2 expression is inhibited in S-type cells, with a
phosphorothioated antisense oligonucleotide (AS5), then p53 accumulates
in the nucleus and the SH-EP1 cells undergo apoptosis. Surprisingly,
induction of p21 and G1-arrest are not attenuated in S-type
cells, despite the predominantly cytoplasmic location of p53. Whereas,
G1-arrest is attenuated in the SH-SY5Y cells, which have
high levels of nuclear p53. Taken together, these findings suggest
attenuation of G1-arrest is related to the differentiation
status of neuroblastomas and occurs downstream of p53 nuclear
accumulation. These results demonstrate for the first time that
hyperactive nuclear export of p53 attenuates chemotherapy-induced
apoptosis in NB cells, and our findings suggest that inhibitors of MDM2
may enhance the therapeutic efficacy of etoposide by promoting
apoptosis rather than trans-differentiation.
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