Malignant pleural mesotheliomas (
MPMs) are usually wild type for the p53 gene but contain homozygous deletions in the INK4A locus that encodes
p14(ARF), an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of
p14(ARF) expression and the presence of SV40
large T antigen (L-Tag) result in p53 inactivation in MPM. We did not detect SV40 L-Tag
mRNA in either MPM cell lines or primary cultures, and treatment of p14(ARF)-deficient cells with
cisplatin (CDDP) increased both total and phosphorylated p53 and enhanced p53
DNA-binding activity. On incubation with CDDP, levels of positively regulated p53 transcriptional targets p21(WAF), PIG3, MDM2, Bax, and PUMA increased in p14(ARF)-deficient cells, whereas negatively regulated
survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14(ARF)-deficient cells, and treatment with p53-specific
siRNA rendered them more CDDP-resistant. p53 was also activated by: 1) inhibition of MDM2 (using
nutlin-3); 2) transient overexpression of
p14(ARF); and 3) targeting of
survivin using
antisense oligonucleotides. However, it is noteworthy that only
survivin downregulation sensitized cells to CDDP-induced apoptosis. These results suggest that p53 is functional in the absence of
p14(ARF) in MPM and that targeting of the downstream apoptosis inhibitor
survivin can sensitize to CDDP-induced apoptosis.