Journal
CELL CYCLE
Volume 10, Issue 10, Pages 1679-1689Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.10.15642
Keywords
mutant p53 reactivation; apoptosis; zinc; p53 transcriptional activity; cancer therapy
Categories
Funding
- Italian Association for Cancer Research (AIRC)
- Yad Abraham for Cancer Therapy
- Flight Attendants Medical Research Institute (FAMRI)
- Italian Foundation for Cancer Research (FIRC)
- EMBO
- L'Oreal Italia-UNESCO for Women in Science
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available