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Reactivation of p53 mutants by p53 reactivation and induction of massive apoptosis in thyroid cancer cells
Author(s) -
Messina Rosa Linda,
Sanfilippo Mariangela,
Vella Veronica,
Pandini Giuseppe,
Vigneri Paolo,
Nicolosi Maria Luisa,
Gianì Fiorenza,
Vigneri Riccardo,
Frasca Francesco
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26228
Subject(s) - thyroid cancer , apoptosis , cancer research , biology , cancer cell , cancer , thyroid , cytotoxic t cell , microbiology and biotechnology , endocrinology , in vitro , genetics
Most undifferentiated thyroid carcinomas express p53 mutants and thereafter, are very resistant to chemotherapy. p53 reactivation and induction of massive apoptosis (Prima‐1) is a compound restoring the tumor‐suppressor activity of p53 mutants. We tested the effect of Prima‐1 in thyroid cancer cells harboring p53 mutations. Increasing doses of Prima‐1 reduced viability of thyroid cancer cells at a variable extent (range 20–80%). Prima‐1 up‐regulated p53 target genes (p21 WAF1 , BCL2‐associated X protein (Bax), and murine double minute 2 (MDM2)), in BC‐PAP and Hth‐74 cells (expressing D259Y/K286E and K286E p53 mutants) but had no effect in SW1736 (p53 null) and TPC‐1 (expressing wild‐type p53) thyroid cancer cells. Prima‐1 also increased the cytotoxic effects of either doxorubicin or cisplatin in thyroid cancer cells, including the chemo‐resistant 8305C, Hth‐74 and BC‐PAP cells. Moreover, real‐time PCR and Western blot indicated that Prima‐1 increases the mRNA of thyroid‐specific differentiation markers in thyroid cancer cells. Fluorescence‐activated cell sorting analysis revealed that Prima‐1 effect on thyroid cancer cells occurs via the enhancement of both cell cycle arrest and apoptosis. Small interfering RNA experiments indicated that Prima‐1 effect is mediated by p53 mutants but not by the p53 paralog p73. Moreover, in C‐643 thyroid cancer cells, forced to ectopically express wild‐type p53, Prima‐1 prevented the dominant negative effect of double K248Q/K286E p53 mutant. Finally, co‐IP experiments indicated that in Hth‐74 cells Prima‐1 prevents the ability of p53 mutants to sequestrate the p53 paralog TAp73. These in vitro studies imply that p53 mutant reactivation by small compounds may become a novel anticancer therapy in undifferentiated thyroid carcinomas.