Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 6, Pages 1080-1091Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0626
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R00HD059985]
- The National Cancer Institute [R01CA197976]
- The Olson Center for Women's Health
- The Fred & Pamela Buffett Cancer Center [LB595]
- The Colleen's Dream Foundation
- The Marsha Rivkin Center for Cancer Research
- COBRE Grant from the Nebraska Center for Cell Signaling/NIGMS [5P30GM106397-02]
- Department of Veterans Affairs Research and Development Program
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G-protein-coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown, and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the current study, we provide convincing in vitro and in vivo evidence that G-1 is able to suppress the growth of breast cancer cells independent of the expression status of GPERs and classic estrogen receptors. Interestingly, we found that triple-negative breast cancer cells (TNBC) are very sensitive to G-1 treatment. We found that G-1 arrested the cell cycle in the prophase of mitosis, leading to caspase activation and apoptosis of breast cancer cells. Our mechanistic studies indicated that G-1, similar to colchicine and 2-methoxyestradiol, binds to colchicine binding site on tubulin, inhibiting tubulin polymerization and subsequent assembly of normal mitotic spindle apparatus during breast cancer cell mitosis. Therefore, G-1 is a novel microtubule-targeting agent and could be a promising anti-microtubule drug for breast cancer treatment, especially for TNBC treatment. (C) 2017 AACR.
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