Assessment of Enoxacin Effect on Cancer Growth and Microrna Expression in Prostate Cell Lines
Background: Prostate cancer (PCa) is one of the most incident malignancies worldwide and represents a leading cause of cancer-related morbidity and mortality.Although efficient therapy is available for early-stage PCa, treatment of advanced diseaseis mainly ineffective and remains a clinical challen...
Saved in:
| Main Author: | |
|---|---|
| Format: | Dissertation |
| Language: | English |
| Published: |
ProQuest Dissertations & Theses
01-01-2012
|
| Subjects: | |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background: Prostate cancer (PCa) is one of the most incident malignancies worldwide and represents a leading cause of cancer-related morbidity and mortality.Although efficient therapy is available for early-stage PCa, treatment of advanced diseaseis mainly ineffective and remains a clinical challenge. Thus, new therapeutic strategies,based on the biology of PCa, are urgently needed. MicroRNA (miRNA) dysregulation is associated with PCa development and progression. In fact, several studies have reporteda widespread downregulation of miRNAs in this disease, which highlights the importance of studying compounds with the ability to restore the global miRNA expression.Aims: The main aim of this study was to define the usefulness of enoxacin as ananti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in a Transactivator RNA-binding protein (TRBP)-mediated manner.Material and Methods: A panel of five PCa cell lines was screened for TARBP2mutations by direct sequencing and the protein levels of TRBP were evaluated byWestern Blot. Immunohisto chemistry was performed to assess the protein levels of TRBPin primary prostate carcinomas. After exposure of PCa cell lines to enoxacin, cell viability,apoptosis, cell cycle, and cell invasion assays were carried out to evaluate the effects ofthe drug. A miRCURY LNA™ array was used to determine the impact of enoxacin on theexpression profile of miRNAs. Then, the protein levels of histone deacetylase 1 (HDAC1),a direct target of one of the overexpressed miRNAs, were assessed by Western Blot.Results and Discussion: All PCa cell lines analyzed were TARBP2wild-type and expressed TRBP protein. Furthermore, primary prostate carcinomas displayed normal levels of TRBP protein, rendering them sensitive to restoration of normal miRNA biogenesis by enoxacin. Remarkably, enoxacin was able to decrease cell viability, induceapoptosis, lead to cell cycle arrest, and inhibit the invasive potential of PCa cell lines.Enoxacin was also effective in restoring the global expression of miRNAs, enhancing the expression of tumor-suppressor miRNAs in PCa. Moreover, the over expression of miR449a, one of the tumor-suppressor miRNAs implicated in PCa, was associated with the downregulation of its direct target oncoprotein, HDAC1.Conclusions: These results demonstrated that PCa cells are highly responsive to the anti-tumoral effects of enoxacin. Therefore, enoxacin constitutes a promising therapeutic agent andin vivostudies should be performed to further support the potential of enoxacin for PCa treatment. |
|---|---|
| ISBN: | 9798382670706 |