Overexpression of COX-2 in Celecoxib-Resistant Breast Cancer Cell Lines
| Autor: | Anthony Lucci, Karen Tai, Balraj Singh, LaTashia R. Irving |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_treatment
Breast Neoplasms Inflammatory breast cancer Article Metastasis Targeted therapy Breast cancer Cell Line Tumor medicine Humans skin and connective tissue diseases Sulfonamides Cyclooxygenase 2 Inhibitors business.industry Cancer medicine.disease Proto-Oncogene Proteins c-bcl-2 Celecoxib Cyclooxygenase 2 Drug Resistance Neoplasm Cell culture Cancer cell Immunology Cancer research Pyrazoles Female lipids (amino acids peptides and proteins) Surgery Breast disease business Signal Transduction |
| Zdroj: | Journal of Surgical Research. 163:235-243 |
| ISSN: | 0022-4804 |
| DOI: | 10.1016/j.jss.2010.04.061 |
| Popis: | Cyclooxygenase-2 (COX-2) plays a key role in breast cancer progression and metastasis. Effective therapeutic targeting of COX-2 would require the knowledge of whether a tumor is addicted to COX-2, and if we can counter the potential resistance to anti-COX-2 therapy. Herein we tested the hypothesis that celecoxib-resistance involves selection of cancer cells that overexpress COX-2.We selected celecoxib-resistant (CER) variants from two metastatic cell lines, SUM149 inflammatory breast cancer (IBC) cell line and MDA-MB-231-BSC60 cell line, by culturing them in the presence of celecoxib. We measured the relative levels of COX-2 protein and its network components Bcl-2, Bcl-xL, and Bax in the parental cell lines and their CER variants by Western blotting. To determine whether celecoxib resistance would increase tumorigenicity, we performed an in vitro clonogenicity assay. We determined the statistical significance of differences between the groups using the two-sample t-test.Both the celecoxib-resistant cell lines SUM149-CER and BSC60-CER produced significantly higher levels of COX-2 protein than their parental counterparts (P0.05). The CER variants produced a reduced level of pro-apoptosis protein Bax (both cell lines) and increased levels of anti-apoptosis proteins Bcl-2 (BSC60) or Bcl-xL (SUM149). Importantly, the CER variants had significantly higher clonogenicity than their parental cell lines (P0.05). The siRNA-mediated COX-2 knockdown in SUM149-CER cell line resulted in a significant decrease in clonogenicity and in Bcl-xL and Bcl-2 protein levels, thus supporting our hypothesis.Celecoxib-resistant variant cells present in breast cancer cell lines overexpress COX-2, which is robustly linked with survival pathways and clonogenicity. Since COX-2 is important in the variant cancer cells of aggressive nature, it represents a good therapeutic target. |
| Databáze: | OpenAIRE |
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