Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lei
L
Wang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yang
Y
Yu
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Dar-Chone
DC
Chow
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Fei
F
Yan
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chih-Chao
CC
Hsu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Fabio
F
Stossi
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Michael A
MA
Mancini
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Timothy
T
Palzkill
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lan
L
Liao
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Suoling
S
Zhou
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Jianming
J
Xu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: dlonard@bcm.edu.
David M
DM
Lonard
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: berto@bcm.edu.
Bert W
BW
O'Malley
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D015394:Molecular Structure; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C000602902:4-ethyl-2,6-bispyridin-3-ylmethylenecyclohexanone; D003512:Cyclohexanones; D051958:Nuclear Receptor Coactivator 2; D011725:Pyridines; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3