Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation
Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non–small-cell lung cancer (NSCLC); unfortun...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-11-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222010940 |
| _version_ | 1797986433054539776 |
|---|---|
| author | Dai Cao Die Chen Jiang-Nan Xia Wen-Yan Wang Guo-Yuan Zhu Li-Wen Chen Chuantao Zhang Bo Tan Hui Li Ying-Wei Li |
| author_facet | Dai Cao Die Chen Jiang-Nan Xia Wen-Yan Wang Guo-Yuan Zhu Li-Wen Chen Chuantao Zhang Bo Tan Hui Li Ying-Wei Li |
| author_sort | Dai Cao |
| collection | DOAJ |
| description | Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non–small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1–induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell–like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ–TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling. |
| first_indexed | 2024-04-11T07:32:40Z |
| format | Article |
| id | doaj.art-13c6906933c846ea9c6ac806ba133309 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T07:32:40Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-13c6906933c846ea9c6ac806ba1333092022-12-22T04:36:49ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-11-01155113705Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradationDai Cao0Die Chen1Jiang-Nan Xia2Wen-Yan Wang3Guo-Yuan Zhu4Li-Wen Chen5Chuantao Zhang6Bo Tan7Hui Li8Ying-Wei Li9Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaResearch Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaResearch Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaResearch Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, ChinaArtemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, ChinaDepartment of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaResearch Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Correspondence to: Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Correspondence to: Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Correspondence to: Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non–small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1–induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell–like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ–TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling.http://www.sciencedirect.com/science/article/pii/S0753332222010940Anti-tumor immunityArtesunateEGFR-TKI resistanceNon-small-cell lung cancerPD-L1TAZ |
| spellingShingle | Dai Cao Die Chen Jiang-Nan Xia Wen-Yan Wang Guo-Yuan Zhu Li-Wen Chen Chuantao Zhang Bo Tan Hui Li Ying-Wei Li Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation Biomedicine & Pharmacotherapy Anti-tumor immunity Artesunate EGFR-TKI resistance Non-small-cell lung cancer PD-L1 TAZ |
| title | Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation |
| title_full | Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation |
| title_fullStr | Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation |
| title_full_unstemmed | Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation |
| title_short | Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation |
| title_sort | artesunate promoted anti tumor immunity and overcame egfr tki resistance in non small cell lung cancer by enhancing oncogenic taz degradation |
| topic | Anti-tumor immunity Artesunate EGFR-TKI resistance Non-small-cell lung cancer PD-L1 TAZ |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222010940 |
| work_keys_str_mv | AT daicao artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT diechen artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT jiangnanxia artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT wenyanwang artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT guoyuanzhu artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT liwenchen artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT chuantaozhang artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT botan artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT huili artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation AT yingweili artesunatepromotedantitumorimmunityandovercameegfrtkiresistanceinnonsmallcelllungcancerbyenhancingoncogenictazdegradation |