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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Neoplastic
  • Glycolysis / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Islet Amyloid Polypeptide / agonists
  • Islet Amyloid Polypeptide / genetics
  • Islet Amyloid Polypeptide / metabolism
  • Islet Amyloid Polypeptide / pharmacology*
  • Lymphoma / drug therapy*
  • Lymphoma / genetics
  • Lymphoma / mortality
  • Lymphoma / pathology
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics*
  • Phosphoric Monoester Hydrolases
  • Proteins / agonists
  • Proteins / genetics
  • Proteins / metabolism
  • Signal Transduction
  • Survival Analysis
  • Thymus Neoplasms / drug therapy*
  • Thymus Neoplasms / genetics
  • Thymus Neoplasms / mortality
  • Thymus Neoplasms / pathology
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Transaminases / genetics
  • Transaminases / metabolism
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*


  • Anticarcinogenic Agents
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Hypoglycemic Agents
  • Islet Amyloid Polypeptide
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • TP73 protein, human
  • Trans-Activators
  • Trp63 protein, mouse
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • delta Np73 protein, human
  • pramlintide
  • Transaminases
  • glutamine-pyruvate aminotransferase
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, mouse