E3 Ubiquitin Ligase <i>TRIP12</i> Controls Exit from Mitosis via Positive Regulation of <i>MCL-1</i> in Response to Taxol
<p dir="ltr">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<...
محفوظ في:
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| مؤلفون آخرون: | , , |
| منشور في: |
2023
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| الملخص: | <p dir="ltr">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 TRIP12 via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of TRIP12 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 MCL-1 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/FBW7/MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.</p><h2>Other Information</h2><p dir="ltr">Published in: Cancers<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/cancers15020505" target="_blank">https://dx.doi.org/10.3390/cancers15020505</a></p> |
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