title: 3,4-Methylenedioxy-β-nitrostyrene inhibits adhesion and migration of human triple-negative breast cancer cells by suppressing β1 integrin function and surface protein disulfide isomerase.
abstract: Triple negative breast cancer (TNBC) exhibits an aggressive clinical course by high metastatic potential. It is known that integrin-mediated cell adhesion and migration are important for cancer metastasis. In the present study, a synthetic compound, 3, 4-methyenedioxy-β-nitrostyrene (MNS), significantly inhibited adhesion of TNBC cell lines to different extracellular matrix (ECM) components. The antimetastatic capacity of MNS was also observed through reducing TNBC cells migration and invasion without affecting cell viability. Confocal microscopy revealed that MNS disrupted the formation of focal adhesion complex and actin stress fiber networks. Consistent with this finding, MNS inhibited phosphorylation of focal adhesion kinase (FAK) and paxillin as detected by Western blot analysis. In exploring the underlying mechanism, we found that MNS inhibited phosphorylation of FAK as a result of reducing β1 integrin activation and clustering. A cell-impermeable dithiol reagent, 2, 3-dimercaptopropane-1-sulfonic acid abrogated all of MNS's actions, indicating that MNS may react with thiol groups of cell surface proteins that are involved in regulation of β1 integrin function as well as cell adhesion and migration. Cell surface protein disulfide isomerase (PDI) has been reported to be essential for the affinity modulation of β integrins. We also demonstrated that MNS inhibited PDI activity both in a pure enzyme system and in intact cancer cells. Taken together, our results suggest that MNS inhibits in vitro metastatic properties of TNBC cells through suppression of β1 integrin activation and focal adhesion signaling. Moreover, inhibition of surface PDI may contribute, at least in part, to the actions of MNS. These results suggest that MNS has a potential to be developed as an anticancer agent for treatment of TNBC.
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan. Electronic address: yachwu@mail.cmu.edu.tw.
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Po-Hsiung
authors.initials: PH
authors.lastname: Kung
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan. Electronic address: ccwu@kmu.edu.tw.
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004148:Dioxolanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
chemical_list: C514815:3,4-methylenedioxy-beta-nitrostyrene; D000970:Antineoplastic Agents; D000975:Antioxidants; D004148:Dioxolanes; D019012:Integrin beta1; D013438:Sulfhydryl Compounds; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019704:Protein Disulfide-Isomerases
keywords: 3,4-Methylenedioxy-β-nitrostyrene (MNS); Metastasis; Protein disulfide isomerase; Triple-negative breast cancer; β1 integrin