ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels
The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/2/945 |
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| author | Seyedeh Zahra Dehghanian Cheng-Tang Pan Jasmine Marianne Lee Yow-Ling Shiue |
| author_facet | Seyedeh Zahra Dehghanian Cheng-Tang Pan Jasmine Marianne Lee Yow-Ling Shiue |
| author_sort | Seyedeh Zahra Dehghanian |
| collection | DOAJ |
| description | The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G<sub>2</sub>/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial–mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed <i>S-phase kinase associated protein</i> 2 (<i>SKP2</i>) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for <i>SKP2</i> transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of <i>SKP2</i> at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins. |
| first_indexed | 2024-03-09T04:19:43Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:19:43Z |
| publishDate | 2021-01-01 |
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| spelling | doaj.art-fee0d6be17604bc7a3f55a6480767f8a2023-12-03T13:49:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122294510.3390/ijms22020945ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational LevelsSeyedeh Zahra Dehghanian0Cheng-Tang Pan1Jasmine Marianne Lee2Yow-Ling Shiue3Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 70 Lienhai Rd, Kaohsiung 80424, TaiwanInstitute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 80424, TaiwanJohns Hopkins University, Baltimore, MD 21218, USAInstitute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 70 Lienhai Rd, Kaohsiung 80424, TaiwanThe objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G<sub>2</sub>/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial–mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed <i>S-phase kinase associated protein</i> 2 (<i>SKP2</i>) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for <i>SKP2</i> transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of <i>SKP2</i> at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.https://www.mdpi.com/1422-0067/22/2/945ABT-751cytostasis<i>S-phase kinase associated protein 2</i>AKTcyclin-dependent kinase inhibitors |
| spellingShingle | Seyedeh Zahra Dehghanian Cheng-Tang Pan Jasmine Marianne Lee Yow-Ling Shiue ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels International Journal of Molecular Sciences ABT-751 cytostasis <i>S-phase kinase associated protein 2</i> AKT cyclin-dependent kinase inhibitors |
| title | ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels |
| title_full | ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels |
| title_fullStr | ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels |
| title_full_unstemmed | ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels |
| title_short | ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of <i>SKP2</i> at Both Transcriptional and Post-Translational Levels |
| title_sort | abt 751 induces multiple anticancer effects in urinary bladder urothelial carcinoma derived cells highlighting the induction of cytostasis through the inhibition of i skp2 i at both transcriptional and post translational levels |
| topic | ABT-751 cytostasis <i>S-phase kinase associated protein 2</i> AKT cyclin-dependent kinase inhibitors |
| url | https://www.mdpi.com/1422-0067/22/2/945 |
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