E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol
Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to t...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/2/505 |
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| author | Kripa S. Keyan Rania Alanany Amira Kohil Omar M. Khan |
| author_facet | Kripa S. Keyan Rania Alanany Amira Kohil Omar M. Khan |
| author_sort | Kripa S. Keyan |
| collection | DOAJ |
| description | Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to the accumulation of its substrate <i>MCL-1</i> which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase <i>TRIP12</i> is a negative regulator of <i>FBW7</i> protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by <i>TRIP12</i> via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of <i>TRIP12</i> accelerates <i>MCL-1</i> protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of <i>FBW7</i> to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of <i>MCL-1</i> protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, <i>TRIP12</i> deletion leads to enhanced mitotic arrest and cell death in an <i>FBW7</i> and <i>MCL-1</i> dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the <i>TRIP12</i>/<i>FBW7</i>/<i>MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer. |
| first_indexed | 2024-03-09T13:17:00Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T13:17:00Z |
| publishDate | 2023-01-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f5efeca08d4d410db690379cb1a91f962023-11-30T21:34:50ZengMDPI AGCancers2072-66942023-01-0115250510.3390/cancers15020505E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to TaxolKripa S. Keyan0Rania Alanany1Amira Kohil2Omar M. Khan3Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, QatarChemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to the accumulation of its substrate <i>MCL-1</i> which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase <i>TRIP12</i> is a negative regulator of <i>FBW7</i> protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by <i>TRIP12</i> via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of <i>TRIP12</i> accelerates <i>MCL-1</i> protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of <i>FBW7</i> to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of <i>MCL-1</i> protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, <i>TRIP12</i> deletion leads to enhanced mitotic arrest and cell death in an <i>FBW7</i> and <i>MCL-1</i> dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the <i>TRIP12</i>/<i>FBW7</i>/<i>MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.https://www.mdpi.com/2072-6694/15/2/505<i>FBW7</i><i>MCL-1</i>chemotherapyTaxolproteasomal degradationmitotic arrest |
| spellingShingle | Kripa S. Keyan Rania Alanany Amira Kohil Omar M. Khan E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol Cancers <i>FBW7</i> <i>MCL-1</i> chemotherapy Taxol proteasomal degradation mitotic arrest |
| title | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_full | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_fullStr | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_full_unstemmed | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_short | E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol |
| title_sort | e3 ubiquitin ligase i trip12 i controls exit from mitosis via positive regulation of i mcl 1 i in response to taxol |
| topic | <i>FBW7</i> <i>MCL-1</i> chemotherapy Taxol proteasomal degradation mitotic arrest |
| url | https://www.mdpi.com/2072-6694/15/2/505 |
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