Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right?
Abstract Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301434 |
| _version_ | 1797742683067777024 |
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| author | Xinran Shen Yudi Deng Liqiang Chen Chendong Liu Lian Li Yuan Huang |
| author_facet | Xinran Shen Yudi Deng Liqiang Chen Chendong Liu Lian Li Yuan Huang |
| author_sort | Xinran Shen |
| collection | DOAJ |
| description | Abstract Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER‐targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER‐related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER‐targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial–mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER‐targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER‐targeting therapy benefits from the autophagy‐enhancing strategy more than the autophagy‐inhibiting strategy for antitumor and antimetastasis treatment. |
| first_indexed | 2024-03-12T14:44:06Z |
| format | Article |
| id | doaj.art-8d4962b118104c1ba59cd6b52d611472 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T14:44:06Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-8d4962b118104c1ba59cd6b52d6114722023-08-16T02:23:01ZengWileyAdvanced Science2198-38442023-08-011023n/an/a10.1002/advs.202301434Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right?Xinran Shen0Yudi Deng1Liqiang Chen2Chendong Liu3Lian Li4Yuan Huang5Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaKey Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaKey Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaKey Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaKey Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaKey Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 ChinaAbstract Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER‐targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER‐related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER‐targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial–mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER‐targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER‐targeting therapy benefits from the autophagy‐enhancing strategy more than the autophagy‐inhibiting strategy for antitumor and antimetastasis treatment.https://doi.org/10.1002/advs.202301434antimetastasis therapyautophagy modulationdrug delivery systemendoplasmic reticulum targetingimmunotherapy |
| spellingShingle | Xinran Shen Yudi Deng Liqiang Chen Chendong Liu Lian Li Yuan Huang Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? Advanced Science antimetastasis therapy autophagy modulation drug delivery system endoplasmic reticulum targeting immunotherapy |
| title | Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? |
| title_full | Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? |
| title_fullStr | Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? |
| title_full_unstemmed | Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? |
| title_short | Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right? |
| title_sort | modulation of autophagy direction to enhance antitumor effect of endoplasmic reticulum targeted therapy left or right |
| topic | antimetastasis therapy autophagy modulation drug delivery system endoplasmic reticulum targeting immunotherapy |
| url | https://doi.org/10.1002/advs.202301434 |
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