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Cell Cycle. 2016;15(2):164-71. doi: 10.1080/15384101.2015.1121333.

Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73.

Author information

1
a Department of Molecular and Cellular Oncology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
2
b Department of Translational Molecular Pathology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
3
c Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center , Houston , TX USA.
4
d Department of Veterinary Medicine and Surgery , The University of Texas M.D. Anderson Cancer Center , Houston ; TX , USA.

Abstract

TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. (1,2) Therapeutic strategies to reactivate the p53-pathway have been challenging, (3,4) and no effective treatment exists. (5) We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and ΔN isoforms. We recently demonstrated that deletion of either ΔNp63 or ΔNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both ΔNp63 and ΔNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both ΔNp63 and ΔNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in ΔNp63/ΔNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target ΔNp63 and ΔNp73 to treat cancer patients with alterations in p53.

KEYWORDS:

p53 family; targeted therapy; tumor suppressors

PMID:
26652033
PMCID:
PMC4825839
DOI:
10.1080/15384101.2015.1121333
[Indexed for MEDLINE]
Free PMC Article

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