Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture
The acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can efficiently k...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3944 |
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| author | Lili Xu Bijia Su Lijun Mo Chenye Zhao Zhenlin Zhao Hongwei Li Zhiming Hu Jinlong Li |
| author_facet | Lili Xu Bijia Su Lijun Mo Chenye Zhao Zhenlin Zhao Hongwei Li Zhiming Hu Jinlong Li |
| author_sort | Lili Xu |
| collection | DOAJ |
| description | The acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can efficiently kill bladder cancer (BC) cells in acidic culture, and more intriguingly, NCTD can induce immunogenic cell death (ICD), thereby promoting antitumor immunity. In NCTD-treated BC cells, the surface-exposed calreticulin (ecto-CALR) was significantly increased. Consistently, co-culture with these cells promoted dendritic cell (DC) maturation. The NCTD-induced ICD is autophagy dependent, as autophagy inhibition completely blocked the NCTD-induced ecto-CALR and DC maturation. In addition, the DC showed a distinct maturation phenotype (CD80<sup>high</sup> CD86<sup>low</sup>) in acidic culture, as compared to that in physiological pH (CD<sup>80</sup> high CD86<sup>high</sup>). Finally, the NCTD-induced ICD was validated in a mouse model. NCTD treatment significantly increased the tumor-infiltrating T lymphocytes in MB49 bladder cancer mice. Immunizing mice with NCTD-treated MB49 cells significantly increased tumor-free survival as compared to control. These findings demonstrate that NCTD could induce ICD in an acidic environment and suggest the feasibility to combine NCTD with anticancer immunotherapy to treat BC. |
| first_indexed | 2024-03-09T11:44:53Z |
| format | Article |
| id | doaj.art-d07a8a8c250541ca8622074d5493fd2f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:44:53Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d07a8a8c250541ca8622074d5493fd2f2023-11-30T23:24:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01237394410.3390/ijms23073944Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic CultureLili Xu0Bijia Su1Lijun Mo2Chenye Zhao3Zhenlin Zhao4Hongwei Li5Zhiming Hu6Jinlong Li7Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaInstitute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaInstitute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaShenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, 14 Jinhui Road, Shenzhen 518118, ChinaShenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, 14 Jinhui Road, Shenzhen 518118, ChinaInstitute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaInstitute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaInstitute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaThe acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can efficiently kill bladder cancer (BC) cells in acidic culture, and more intriguingly, NCTD can induce immunogenic cell death (ICD), thereby promoting antitumor immunity. In NCTD-treated BC cells, the surface-exposed calreticulin (ecto-CALR) was significantly increased. Consistently, co-culture with these cells promoted dendritic cell (DC) maturation. The NCTD-induced ICD is autophagy dependent, as autophagy inhibition completely blocked the NCTD-induced ecto-CALR and DC maturation. In addition, the DC showed a distinct maturation phenotype (CD80<sup>high</sup> CD86<sup>low</sup>) in acidic culture, as compared to that in physiological pH (CD<sup>80</sup> high CD86<sup>high</sup>). Finally, the NCTD-induced ICD was validated in a mouse model. NCTD treatment significantly increased the tumor-infiltrating T lymphocytes in MB49 bladder cancer mice. Immunizing mice with NCTD-treated MB49 cells significantly increased tumor-free survival as compared to control. These findings demonstrate that NCTD could induce ICD in an acidic environment and suggest the feasibility to combine NCTD with anticancer immunotherapy to treat BC.https://www.mdpi.com/1422-0067/23/7/3944norcantharidinimmunogenic cell deathautophagyacidic extracellular pHbladder cancer |
| spellingShingle | Lili Xu Bijia Su Lijun Mo Chenye Zhao Zhenlin Zhao Hongwei Li Zhiming Hu Jinlong Li Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture International Journal of Molecular Sciences norcantharidin immunogenic cell death autophagy acidic extracellular pH bladder cancer |
| title | Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture |
| title_full | Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture |
| title_fullStr | Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture |
| title_full_unstemmed | Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture |
| title_short | Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture |
| title_sort | norcantharidin induces immunogenic cell death of bladder cancer cells through promoting autophagy in acidic culture |
| topic | norcantharidin immunogenic cell death autophagy acidic extracellular pH bladder cancer |
| url | https://www.mdpi.com/1422-0067/23/7/3944 |
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