Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy

Nat Commun. 2014 Nov 17;5:5476. doi: 10.1038/ncomms6476.

Abstract

The progression of many solid tumours is driven by deregulation of multiple common pathways, particularly Rb, PI(3)K/Akt and p53. Prior studies identified TopBP1 as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis. Here we perform a molecular docking screening and identify a lead compound, calcein, capable of blocking TopBP1 oligomerization and p53 binding, resulting in re-activation of E2F1-dependent apoptosis and blockade of mutp53 gain-of-function. Calcein AM, the cell-permeable derivative of calcein, shows significant antitumour activity in a wide spectrum of cultured cancer cells harbouring high TopBP1 levels. These biochemical findings are recapitulated in breast cancer xenograft models. Thus, our study provides proof-of-concept evidence for targeting TopBP1, a convergent point of multiple pathways, as a cancer therapy.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / physiopathology
  • Carrier Proteins / drug effects*
  • Carrier Proteins / physiology
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / physiology
  • E2F1 Transcription Factor / metabolism
  • E2F1 Transcription Factor / physiology
  • Female
  • Fluoresceins / metabolism
  • Gene Expression Regulation, Neoplastic / physiology
  • Heterografts
  • Humans
  • Mice
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / physiopathology
  • Nuclear Proteins / drug effects*
  • Nuclear Proteins / physiology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Fluoresceins
  • Nuclear Proteins
  • TOPBP1 protein, human
  • Tumor Suppressor Protein p53
  • fluorexon