RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer
Abstract The RNA-binding protein Hu antigen R (HuR) plays a pivotal role in cancer progression, and previous studies have demonstrated its involvement in suppressing cell death in cancer. However, the precise mechanisms underlying HuR inhibition-induced cell death remain elusive. Here, we investigat...
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BMC
2024-12-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01916-z |
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| author | Lanjing Wei Sung Hae Kim Ahlam M. Armaly Jeffrey Aubé Liang Xu Xiaoqing Wu |
| author_facet | Lanjing Wei Sung Hae Kim Ahlam M. Armaly Jeffrey Aubé Liang Xu Xiaoqing Wu |
| author_sort | Lanjing Wei |
| collection | DOAJ |
| description | Abstract The RNA-binding protein Hu antigen R (HuR) plays a pivotal role in cancer progression, and previous studies have demonstrated its involvement in suppressing cell death in cancer. However, the precise mechanisms underlying HuR inhibition-induced cell death remain elusive. Here, we investigated the impacts of HuR functional inhibition via the small molecule inhibitor KH-3 on cell proliferation, colony formation, and cell death across multiple cancer cell lines, with an emphasis on breast and prostate cancers. KH-3 treatment induced apoptotic cell death of various cancer cell lines, as well as autophagy-associated cell death and ferroptosis. Remarkably, KH-3-induced cell death was partially rescued by an autophagy inhibitor and a ferroptosis inhibitor. The anti-tumor effects of KH-3 were further validated in two mouse xenograft models of human prostate cancer. Mechanistically, KH-3 reduced the expression of HuR targets involved in apoptosis and ferroptosis suppression, including cFLIP and SLC7A11, respectively. Moreover, cFLIP silencing enhanced Caspase-8 activation as well as PARP cleavage in both breast cancer and prostate cancer cells. Both KH-3-induced pharmacological HuR inhibition and RNA interference-mediated HuR knockdown reduced the expression of SLC7A11. Additionally, KH-3 also reduced XIAP and Survivin, enhancing the activation of multiple caspases and leading to apoptosis. This study highlights the critical roles of HuR in programmed cell death regulation, advocating HuR inhibition as a promising anti-tumor strategy for cell-death-inducing cancer therapy. |
| format | Article |
| id | doaj-art-81353faa4ece45169487dba6f78ea535 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-81353faa4ece45169487dba6f78ea5352024-12-08T12:38:05ZengBMCCell Communication and Signaling1478-811X2024-12-0122111410.1186/s12964-024-01916-zRNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancerLanjing Wei0Sung Hae Kim1Ahlam M. Armaly2Jeffrey Aubé3Liang Xu4Xiaoqing Wu5Bioengineering Program, The University of KansasDepartment of Molecular Biosciences, The University of KansasDivision of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, The University of North CarolinaDivision of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, The University of North CarolinaDepartment of Molecular Biosciences, The University of KansasDepartment of Molecular Biosciences, The University of KansasAbstract The RNA-binding protein Hu antigen R (HuR) plays a pivotal role in cancer progression, and previous studies have demonstrated its involvement in suppressing cell death in cancer. However, the precise mechanisms underlying HuR inhibition-induced cell death remain elusive. Here, we investigated the impacts of HuR functional inhibition via the small molecule inhibitor KH-3 on cell proliferation, colony formation, and cell death across multiple cancer cell lines, with an emphasis on breast and prostate cancers. KH-3 treatment induced apoptotic cell death of various cancer cell lines, as well as autophagy-associated cell death and ferroptosis. Remarkably, KH-3-induced cell death was partially rescued by an autophagy inhibitor and a ferroptosis inhibitor. The anti-tumor effects of KH-3 were further validated in two mouse xenograft models of human prostate cancer. Mechanistically, KH-3 reduced the expression of HuR targets involved in apoptosis and ferroptosis suppression, including cFLIP and SLC7A11, respectively. Moreover, cFLIP silencing enhanced Caspase-8 activation as well as PARP cleavage in both breast cancer and prostate cancer cells. Both KH-3-induced pharmacological HuR inhibition and RNA interference-mediated HuR knockdown reduced the expression of SLC7A11. Additionally, KH-3 also reduced XIAP and Survivin, enhancing the activation of multiple caspases and leading to apoptosis. This study highlights the critical roles of HuR in programmed cell death regulation, advocating HuR inhibition as a promising anti-tumor strategy for cell-death-inducing cancer therapy.https://doi.org/10.1186/s12964-024-01916-zHuRCell deathBreast cancerProstate cancerMouse tumor models |
| spellingShingle | Lanjing Wei Sung Hae Kim Ahlam M. Armaly Jeffrey Aubé Liang Xu Xiaoqing Wu RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer Cell Communication and Signaling HuR Cell death Breast cancer Prostate cancer Mouse tumor models |
| title | RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer |
| title_full | RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer |
| title_fullStr | RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer |
| title_full_unstemmed | RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer |
| title_short | RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer |
| title_sort | rna binding protein hur inhibition induces multiple programmed cell death in breast and prostate cancer |
| topic | HuR Cell death Breast cancer Prostate cancer Mouse tumor models |
| url | https://doi.org/10.1186/s12964-024-01916-z |
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