title: G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly.
abstract: 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 convincingin vitroandin vivoevidence 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.Mol Cancer Ther; 16(6); 1080-91. ©2017 AACR.
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Lv
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.|Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei Province, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: He
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Cong
authors.initials: C
authors.lastname: Huang
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.|Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei Province, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Hua
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.|Department of Hepatobiliary Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Remmenga
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Rodabough
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.|Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.|Omaha Veterans Affairs Medical Center, Omaha, Nebraska.
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska. chengwang@unmc.edu.|Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D000970:Antineoplastic Agents; D003517:Cyclopentanes; D011804:Quinolines; D011960:Receptors, Estrogen; D014404:Tubulin; D050257:Tubulin Modulators