Targeting connexin 43 with α–connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1
| Autor: | Joshua Matthew Rhett, Gautam S. Ghatnekar, Jaclynn S. Bruce, Elizabeth S. Yeh, Christina L. Grek, Melissa A. Abt |
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| Jazyk: | angličtina |
| Předmět: |
Cancer Research
Connexin Antineoplastic Agents Breast Neoplasms macromolecular substances Pharmacology Lapatinib 03 medical and health sciences 0302 clinical medicine Breast cancer Drug Delivery Systems Surgical oncology Cell Line Tumor medicine Genetics Connexin43 Humans skin and connective tissue diseases 030304 developmental biology Adaptor Proteins Signal Transducing 0303 health sciences business.industry Gap junction intercellular communication Gap junction Cancer medicine.disease ACT1 peptide Cancer therapeutic Tumor Necrosis Factor Receptor-Associated Peptides and Proteins 3. Good health Tamoxifen Oncology 030220 oncology & carcinogenesis Connexin 43 Cancer research Quinazolines cardiovascular system Female sense organs Stem cell business medicine.drug Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-015-1229-6 |
| Popis: | Background Treatment failure is a critical issue in breast cancer and identifying useful interventions that optimize current cancer therapies remains a critical unmet need. Expression and functional studies have identified connexins (Cxs), a family of gap junction proteins, as potential tumor suppressors. Studies suggest that Cx43 has a role in breast cancer cell proliferation, differentiation, and migration. Although pan-gap junction drugs are available, the lack of specificity of these agents increases the opportunity for off target effects. Consequently, a therapeutic agent that specifically modulates Cx43 would be beneficial and has not been tested in breast cancer. In this study, we now test an agent that specifically targets Cx43, called ACT1, in breast cancer. Methods We evaluated whether direct modulation of Cx43 using a Cx43-directed therapeutic peptide, called ACT1, enhances Cx43 gap junctional activity in breast cancer cells, impairs breast cancer cell proliferation or survival, and enhances the activity of the targeted inhibitors tamoxifen and lapatinib. Results Our results show that therapeutic modulation of Cx43 by ACT1 maintains Cx43 at gap junction sites between cell-cell membrane borders of breast cancer cells and augments gap junction activity in functional assays. The increase in Cx43 gap junctional activity achieved by ACT1 treatment impairs proliferation or survival of breast cancer cells but ACT1 has no effect on non-transformed MCF10A cells. Furthermore, treating ER+ breast cancer cells with a combination of ACT1 and tamoxifen or HER2+ breast cancer cells with ACT1 and lapatinib augments the activity of these targeted inhibitors. Conclusions Based on our findings, we conclude that modulation of Cx43 activity in breast cancer can be effectively achieved with the agent ACT1 to sustain Cx43-mediated gap junctional activity resulting in impaired malignant progression and enhanced activity of lapatinib and tamoxifen, implicating ACT1 as part of a combination regimen in breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1229-6) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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