Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics
Abstract Small molecule inhibitors of apoptosis proteins (IAPs) antagonists, known as Smac mimetics (SMs), activate non-canonical NF-κB and sensitize cancer cells to TNF-induced cell death. SMs are currently in phase III clinical trials for head and neck squamous cell carcinoma (HNSCC) after promisi...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07253-w |
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| author | Yuhan Wang Zijian Liu Qian Si Wanqiu Lu Yuxian Song Wanyong Jin Xihu Yang Zihui Li Xinyang Hu Liang Ding Yue Jing Pei Weng Qiuya Yu Lorraine A. O’Reilly John Silke Xiaoxin Zhang Qingang Hu Yanhong Ni |
| author_facet | Yuhan Wang Zijian Liu Qian Si Wanqiu Lu Yuxian Song Wanyong Jin Xihu Yang Zihui Li Xinyang Hu Liang Ding Yue Jing Pei Weng Qiuya Yu Lorraine A. O’Reilly John Silke Xiaoxin Zhang Qingang Hu Yanhong Ni |
| author_sort | Yuhan Wang |
| collection | DOAJ |
| description | Abstract Small molecule inhibitors of apoptosis proteins (IAPs) antagonists, known as Smac mimetics (SMs), activate non-canonical NF-κB and sensitize cancer cells to TNF-induced cell death. SMs are currently in phase III clinical trials for head and neck squamous cell carcinoma (HNSCC) after promising phase II trials. To explore the utility of SMs in oral squamous cell carcinoma (OSCC), we tested nine human OSCC cell lines and correlated SM sensitivity with both IAP mutation and expression levels. cIAP1 protein expression was shown to be higher in OSCC and a predictor of poor prognosis. However, our in vitro and in vivo testing demonstrated differential sensitivity to SMs, which did not correlate with cIAP1 and cIAP2 expression in these OSCC cell lines. Exogenous TNF failed to effectively increase the sensitivity of SM-resistant OSCC cells to SM-induced cell death. SM resistance was associated with a deficiency in Complex IIa formation, but activation of non-canonical NF-κB was not a determinant of SM efficacy. Finally, metabolic analysis revealed that the ABC transporter pathway was activated in SM-resistant OSSC cells, and SMs combined with ABC transporter inhibitors improved cell death sensitivity to overcome SM resistance. These studies highlight the therapeutic potential of SMs in OSCC and support patient stratification to improve efficacy with the addition of adjuvant therapy. |
| format | Article |
| id | doaj-art-0c6e0f2270ec4dc6bc017b7e7e512e53 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0c6e0f2270ec4dc6bc017b7e7e512e532025-08-20T02:33:06ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111510.1038/s41419-024-07253-wComplex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimeticsYuhan Wang0Zijian Liu1Qian Si2Wanqiu Lu3Yuxian Song4Wanyong Jin5Xihu Yang6Zihui Li7Xinyang Hu8Liang Ding9Yue Jing10Pei Weng11Qiuya Yu12Lorraine A. O’Reilly13John Silke14Xiaoxin Zhang15Qingang Hu16Yanhong Ni17Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversitySchool of Biopharmacy, China Pharmaceutical UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityDepartment of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityDepartment of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing UniversityCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing UniversityAbstract Small molecule inhibitors of apoptosis proteins (IAPs) antagonists, known as Smac mimetics (SMs), activate non-canonical NF-κB and sensitize cancer cells to TNF-induced cell death. SMs are currently in phase III clinical trials for head and neck squamous cell carcinoma (HNSCC) after promising phase II trials. To explore the utility of SMs in oral squamous cell carcinoma (OSCC), we tested nine human OSCC cell lines and correlated SM sensitivity with both IAP mutation and expression levels. cIAP1 protein expression was shown to be higher in OSCC and a predictor of poor prognosis. However, our in vitro and in vivo testing demonstrated differential sensitivity to SMs, which did not correlate with cIAP1 and cIAP2 expression in these OSCC cell lines. Exogenous TNF failed to effectively increase the sensitivity of SM-resistant OSCC cells to SM-induced cell death. SM resistance was associated with a deficiency in Complex IIa formation, but activation of non-canonical NF-κB was not a determinant of SM efficacy. Finally, metabolic analysis revealed that the ABC transporter pathway was activated in SM-resistant OSSC cells, and SMs combined with ABC transporter inhibitors improved cell death sensitivity to overcome SM resistance. These studies highlight the therapeutic potential of SMs in OSCC and support patient stratification to improve efficacy with the addition of adjuvant therapy.https://doi.org/10.1038/s41419-024-07253-w |
| spellingShingle | Yuhan Wang Zijian Liu Qian Si Wanqiu Lu Yuxian Song Wanyong Jin Xihu Yang Zihui Li Xinyang Hu Liang Ding Yue Jing Pei Weng Qiuya Yu Lorraine A. O’Reilly John Silke Xiaoxin Zhang Qingang Hu Yanhong Ni Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics Cell Death and Disease |
| title | Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics |
| title_full | Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics |
| title_fullStr | Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics |
| title_full_unstemmed | Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics |
| title_short | Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics |
| title_sort | complex iia formation and abc transporters determine sensitivity of oscc to smac mimetics |
| url | https://doi.org/10.1038/s41419-024-07253-w |
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