Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression
Abstract Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a c...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202407370 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846116858774683648 |
|---|---|
| author | Yu Gan Qian Hao Tao Han Jing Tong Qingya Yan Hongguang Zhong Bo Gao Yanan Li Zhisheng Xuan Pengfei Li Litong Yao Yingying Xu Yi‐Zhou Jiang Zhi‐Ming Shao Jun Deng Jiaxiang Chen Xiang Zhou |
| author_facet | Yu Gan Qian Hao Tao Han Jing Tong Qingya Yan Hongguang Zhong Bo Gao Yanan Li Zhisheng Xuan Pengfei Li Litong Yao Yingying Xu Yi‐Zhou Jiang Zhi‐Ming Shao Jun Deng Jiaxiang Chen Xiang Zhou |
| author_sort | Yu Gan |
| collection | DOAJ |
| description | Abstract Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre‐rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface‐decorated with iRGD, a tumor‐homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD‐Exo‐siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5‐FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy. |
| format | Article |
| id | doaj-art-f9a0f82fc8024ad5873b23dc3ea7caf0 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-f9a0f82fc8024ad5873b23dc3ea7caf02024-12-18T14:18:10ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202407370Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer ProgressionYu Gan0Qian Hao1Tao Han2Jing Tong3Qingya Yan4Hongguang Zhong5Bo Gao6Yanan Li7Zhisheng Xuan8Pengfei Li9Litong Yao10Yingying Xu11Yi‐Zhou Jiang12Zhi‐Ming Shao13Jun Deng14Jiaxiang Chen15Xiang Zhou16Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University Shanghai 200032 P. R. ChinaFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University Shanghai 200032 P. R. ChinaInstitutes of Health Central Plains, Xinxiang Key laboratory for Molecular Oncology Xinxiang Medical University Xinxiang Henan 453003 P. R. ChinaFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University Shanghai 200032 P. R. ChinaInstitutes of Health Central Plains, Xinxiang Key laboratory for Molecular Oncology Xinxiang Medical University Xinxiang Henan 453003 P. R. ChinaDepartment of Oncology The First Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang Jiangxi 330006 P. R. ChinaUmibio Co. Ltd. Shanghai 201210 P. R. ChinaUmibio Co. Ltd. Shanghai 201210 P. R. ChinaUmibio Co. Ltd. Shanghai 201210 P. R. ChinaLaboratory of Animal Center, Medical Experiment Center Shaanxi University of Chinese Medicine Xianyang 712046 P. R. ChinaDepartment of Breast Surgery The First Hospital of China Medical University Shenyang Liaoning 110001 P. R. ChinaDepartment of Breast Surgery The First Hospital of China Medical University Shenyang Liaoning 110001 P. R. ChinaDepartment of Oncology, Shanghai Medical College Fudan University Shanghai 200032 P. R. ChinaDepartment of Oncology, Shanghai Medical College Fudan University Shanghai 200032 P. R. ChinaDepartment of Oncology The First Affiliated Hospital, Jiangxi Medical College, Nanchang University Nanchang Jiangxi 330006 P. R. ChinaDepartment of Physiology, School of Basic Medical Sciences Jiangxi Medical College, Nanchang University Nanchang 330006 P. R. ChinaFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University Shanghai 200032 P. R. ChinaAbstract Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre‐rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface‐decorated with iRGD, a tumor‐homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD‐Exo‐siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5‐FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy.https://doi.org/10.1002/advs.202407370BRIX1engineered exosomesnucleolar stressp53ribosome biogenesistargeted therapy |
| spellingShingle | Yu Gan Qian Hao Tao Han Jing Tong Qingya Yan Hongguang Zhong Bo Gao Yanan Li Zhisheng Xuan Pengfei Li Litong Yao Yingying Xu Yi‐Zhou Jiang Zhi‐Ming Shao Jun Deng Jiaxiang Chen Xiang Zhou Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression Advanced Science BRIX1 engineered exosomes nucleolar stress p53 ribosome biogenesis targeted therapy |
| title | Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression |
| title_full | Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression |
| title_fullStr | Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression |
| title_full_unstemmed | Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression |
| title_short | Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression |
| title_sort | targeting brix1 via engineered exosomes induces nucleolar stress to suppress cancer progression |
| topic | BRIX1 engineered exosomes nucleolar stress p53 ribosome biogenesis targeted therapy |
| url | https://doi.org/10.1002/advs.202407370 |
| work_keys_str_mv | AT yugan targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT qianhao targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT taohan targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT jingtong targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT qingyayan targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT hongguangzhong targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT bogao targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT yananli targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT zhishengxuan targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT pengfeili targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT litongyao targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT yingyingxu targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT yizhoujiang targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT zhimingshao targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT jundeng targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT jiaxiangchen targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression AT xiangzhou targetingbrix1viaengineeredexosomesinducesnucleolarstresstosuppresscancerprogression |