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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticarcinogenic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics*
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Gene Expression Regulation, Neoplastic
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Glycolysis / drug effects
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Humans
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Hypoglycemic Agents / pharmacology
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Islet Amyloid Polypeptide / agonists
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Islet Amyloid Polypeptide / genetics
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Islet Amyloid Polypeptide / metabolism
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Islet Amyloid Polypeptide / pharmacology*
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Lymphoma / drug therapy*
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Lymphoma / genetics
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Lymphoma / mortality
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Lymphoma / pathology
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Mice
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Mice, Knockout
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics*
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Phosphoproteins / deficiency
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Phosphoproteins / genetics*
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Phosphoric Monoester Hydrolases
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Proteins / agonists
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Proteins / genetics
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Proteins / metabolism
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Signal Transduction
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Survival Analysis
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Thymus Neoplasms / drug therapy*
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Thymus Neoplasms / genetics
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Thymus Neoplasms / mortality
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Thymus Neoplasms / pathology
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Trans-Activators / deficiency
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Trans-Activators / genetics*
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Transaminases / genetics
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Transaminases / metabolism
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Tumor Protein p73
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics*
Substances
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Anticarcinogenic Agents
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Apoptosis Regulatory Proteins
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DNA-Binding Proteins
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Hypoglycemic Agents
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Islet Amyloid Polypeptide
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Nuclear Proteins
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Phosphoproteins
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Proteins
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TP73 protein, human
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Trans-Activators
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Trp63 protein, mouse
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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delta Np73 protein, human
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pramlintide
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Transaminases
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glutamine-pyruvate aminotransferase
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Phosphoric Monoester Hydrolases
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TIGAR protein, mouse