Small Molecule-facilitated Degradation of ANO1 Protein
| Autor: | Jason Borawski, Jeremy L. Jenkins, Michelle Lynn Hall, Christopher Rothwell, Catherine Hodgson, Trixie Wagner, Philippe Piechon, Lewis Whitehead, Scott Tria, Pamela Tranter, Anke Bill, Oana Popa, L. Alex Gaither |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Anticancer Drug
Cell Molecular Modeling Antineoplastic Agents Protein degradation Biochemistry Ion Channels ANO1 Drug Delivery Systems Chloride Channels Protein Degradation Cell Line Tumor Neoplasms ER-associated Degradation medicine Humans Molecular Biology Anoctamin-1 Cancer Biology Cell Proliferation biology Cell growth Computational Biology Cell Biology Cell biology Neoplasm Proteins medicine.anatomical_structure Mechanism of action Cell culture Small Molecules Cancer cell Proteolysis biology.protein Cancer Therapy medicine.symptom Protein A |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: The calcium-activated chloride channel ANO1 is highly expressed in cancer. Results: Inhibition of ANO1 activity alone is not sufficient to inhibit cancer cell proliferation, suggesting a novel function of ANO1 protein in cancer. Conclusion: The ANO1 inhibitor CaCCinh-A01 inhibits cancer cell proliferation by facilitating degradation of ANO1. Significance: Our results may provide a new targeting approach for antitumor therapy in ANO1-amplified cancers. ANO1, a calcium-activated chloride channel, is highly expressed and amplified in human cancers and is a critical survival factor in these cancers. The ANO1 inhibitor CaCCinh-A01 decreases proliferation of ANO1-amplified cell lines; however, the mechanism of action remains elusive. We explored the mechanism behind the inhibitory effect of CaCCinh-A01 on cell proliferation using a combined experimental and in silico approach. We show that inhibition of ANO1 function is not sufficient to diminish proliferation of ANO1-dependent cancer cells. We report that CaCCinh-A01 reduces ANO1 protein levels by facilitating endoplasmic reticulum-associated, proteasomal turnover of ANO1. Washout of CaCCinh-A01 rescued ANO1 protein levels and resumed cell proliferation. Proliferation of newly derived CaCCinh-A01-resistant cell pools was not affected by CaCCinh-A01 as compared with the parental cells. Consistently, CaCCinh-A01 failed to reduce ANO1 protein levels in these cells, whereas ANO1 currents were still inhibited by CaCCinh-A01, indicating that CaCCinh-A01 inhibits cell proliferation by reducing ANO1 protein levels. Furthermore, we employed in silico methods to elucidate novel biological functions of ANO1 inhibitors. Specifically, we derived a pharmacophore model to describe inhibitors capable of promoting ANO1 degradation and report new inhibitors of ANO1-dependent cell proliferation. In summary, our data demonstrate that inhibition of the channel activity of ANO1 is not sufficient to inhibit ANO1-dependent cell proliferation, indicating that the role of ANO1 in cancer only partially depends on its function as a channel. Our results provide an impetus for gaining a deeper understanding of ANO1 modulation in cells and introduce a new targeting approach for antitumor therapy in ANO1-amplified cancers. |
| Databáze: | OpenAIRE |
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