Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy.
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.
Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Pinki
P
Chowdhury
1] Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Computer Science, Rice University, Houston, Texas 77251, USA.
Gregory E
GE
Lin
Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Kang
K
Liu
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Yongcheng
Y
Song
Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Fang-Tsyr
FT
Lin
Section of Hematology/Oncology, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Weei-Chin
WC
Lin
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000378:metabolism / Q000502:physiology; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D005452:Fluoresceins; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human; D016159:Tumor Suppressor Protein p53; C007740:fluorexon