Absence of p53 expression or expression of mutant p53 (mtp53) are common in human
cancers and are associated with increased
cancer resistance to chemo- and
radiotherapy. Therefore, significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway. We previously reported that, in HIPK2 knockdown background, p53 undergoes misfolding with inhibition of
DNA binding and transcriptional activities that correlate with increased chemoresistance, and that
zinc rescues wild-type p53 activity.
Zinc has a crucial role in the biology of p53, in that p53 binds to
DNA through a structurally complex domain stabilized by
zinc atom. In this study, we explored the role of
zinc in p53 reactivation in mutant p53-expressing
cancer cells. We found that
zinc re-established chemosensitivity in
breast cancer SKBR3 (expressing R175H mutation) and
glioblastoma U373MG (expressing R273H mutation) cell lines. Biochemical studies showed that
zinc partly induced the transition of mutant p53
protein (reactive to conformation-sensitive PAb240 antibody for mutant conformation) into a functional conformation (reactive to conformation-sensitive PAb1620 antibody for wild-type conformation).
Zinc-mediated p53 reactivation also reduced the mtp53/p73 interaction restoring both wtp53 and p73 binding to target gene promoters by ChIP assay with in vivo induction of wtp53 target gene expression, which rendered mutant p53 cells more prone to drug killing in vitro. Finally,
zinc administration in U373MG
tumor xenografts increased drug-induced
tumor regression in vivo, which correlated with increased wild-type p53 protein conformation. These results show that the use of
zinc might restore drug sensitivity and inhibit
tumor growth by reactivating mutant p53.