2. Academic Validation
  3. Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death

Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death

  • Cancer Cell. 2015 Aug 10;28(2):240-52. doi: 10.1016/j.ccell.2015.07.005.
Lei Wang 1,  Yang Yu 1,  Dar-Chone Chow 2,  Fei Yan 1,  Chih-Chao Hsu 3,  Fabio Stossi 1,  Michael A Mancini 1,  Timothy Palzkill 2,  Lan Liao 1,  Suoling Zhou 1,  Jianming Xu 1,  David M Lonard 4,  Bert W O'Malley 5
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: dlonard@bcm.edu.
  • 5 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: berto@bcm.edu.
PMID: 26267537 DOI: 10.1016/j.ccell.2015.07.005
Abstract

By integrating growth pathways on which Cancer cells rely, steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) represent emerging targets in Cancer therapeutics. High-throughput screening for Src small molecule inhibitors (SMIs) uncovered MCB-613 as a potent Src small molecule "stimulator" (SMS). We demonstrate that MCB-613 can super-stimulate SRCs' transcriptional activity. Further investigation revealed that MCB-613 increases SRCs' interactions with other coactivators and markedly induces ER stress coupled to the generation of Reactive Oxygen Species (ROS). Because Cancer cells overexpress SRCs and rely on them for growth, we show that we can exploit MCB-613 to selectively induce excessive stress in Cancer cells. This suggests that over-stimulating the Src oncogenic program can be an effective strategy to kill Cancer cells.

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