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: I-Hua Chen, Fang-Rong Chang, Yang-Chang Wu, Po-Hsiung Kung, Chin-Chung Wu
• Journal: Biochimie (Biochimie) Vol. 110 Pg. 81-92 (Mar 2015) ISSN: 1638-6183 [Electronic] France
• PMID: 25593085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• 3,4-methylenedioxy-beta-nitrostyrene
• Antineoplastic Agents
• Antioxidants
• Dioxolanes
• Integrin beta1
• Sulfhydryl Compounds
• Focal Adhesion Protein-Tyrosine Kinases
• Protein Disulfide-Isomerases

Topics

• Antineoplastic Agents (pharmacology)
• Antioxidants (pharmacology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Dioxolanes (pharmacology)
• Down-Regulation (drug effects)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Focal Adhesions (drug effects)
• Humans
• Integrin beta1 (metabolism)
• Neoplasm Invasiveness
• Phosphorylation (drug effects)
• Protein Disulfide-Isomerases (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Sulfhydryl Compounds (pharmacology)
• Triple Negative Breast Neoplasms (pathology)