Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer
| العنوان: | Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer |
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| المؤلفون: | Jeremy Chien, Debarshi Roy, Deok-Beom Jung, Ashwani Khurana, Eleftheria Kalogera, Viji Shridhar, Jamie N. Bakkum-Gamez |
| المصدر: | Scientific Reports Scientific reports, vol 8, iss 1 Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) |
| بيانات النشر: | Nature Publishing Group UK, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell cycle checkpoint, Messenger, lcsh:Medicine, Apoptosis, Sequestosome-1 Protein, 2.1 Biological and endogenous factors, Aetiology, RNA, Small Interfering, lcsh:Science, S-Phase Kinase-Associated Proteins, Cancer, Gene knockdown, Multidisciplinary, Tumor, Chemistry, Cell cycle, 3. Good health, Cell biology, Ovarian Cancer, Gene Expression Regulation, Neoplastic, 5.1 Pharmaceuticals, Quinacrine, Female, Signal transduction, Development of treatments and therapeutic interventions, Cyclin-Dependent Kinase Inhibitor p27, Signal Transduction, Cyclin-Dependent Kinase Inhibitor p21, ATG5, Antineoplastic Agents, Small Interfering, Article, Cell Line, 03 medical and health sciences, Antimalarials, Rare Diseases, Downregulation and upregulation, Cell Line, Tumor, Genetics, Autophagy, Humans, RNA, Messenger, Neoplastic, lcsh:R, Ovary, Drug Repositioning, Cell Cycle Checkpoints, 030104 developmental biology, Orphan Drug, Gene Expression Regulation, RNA, lcsh:Q, Tumor Suppressor Protein p53 |
| الوصف: | We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti-cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs. QC treatment selectively upregulated cell cycle inhibitor p21, and downregulated F box protein Skp2 and p62/SQSTM1 expression independent of p53 status. Genetic downregulation of key autophagy protein ATG5 abolished QC-mediated effects on both cell cycle protein p21/Skp2 as well as autophagic cargo protein p62. Furthermore, genetic silencing of p62/SQSTM1 resulted in increased sensitivity to QC-mediated apoptosis, downregulated Skp2 mRNA and increased accumulation of p21 expression. Likewise, genetic knockdown of Skp2 resulted in the upregulation of p21 and p27 and increased sensitivity of OC cells to QC treatment. In contrast, transient overexpression of exogenous p62-HA plasmid rescued the QC-mediated Skp2 downregulation indicating the positive regulation of Skp2 by p62. Collectively, these data indicate that QC-mediated effects on cell cycle proteins p21/Skp2is autophagy-dependent and p53-independent in high grade serious OC cells. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f232e2b1b8c12bba759dfab4723a991fTest http://europepmc.org/articles/PMC5802832Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f232e2b1b8c12bba759dfab4723a991f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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