IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo

Nature. 2015 Jan 29;517(7536):626-30. doi: 10.1038/nature13910. Epub 2014 Nov 17.

Abstract

TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the ΔN isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the β cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Islet Amyloid Polypeptide / metabolism*
  • Islet Amyloid Polypeptide / pharmacology
  • Islet Amyloid Polypeptide / therapeutic use
  • Lymphoma / drug therapy
  • Lymphoma / genetics
  • Lymphoma / metabolism*
  • Lymphoma / pathology*
  • Male
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Receptor Activity-Modifying Protein 3 / metabolism
  • Receptors, Calcitonin / metabolism
  • Thymus Gland / metabolism
  • Thymus Gland / pathology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / deficiency*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Islet Amyloid Polypeptide
  • Nuclear Proteins
  • Phosphoproteins
  • Receptor Activity-Modifying Protein 3
  • Receptors, Calcitonin
  • Trans-Activators
  • Trp63 protein, mouse
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human
  • pramlintide

Associated data

  • GEO/GSE60827