Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression

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

doi:10.1002/advs.202407370

Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression

Adv Sci (Weinh). 2024 Oct 30:e2407370. doi: 10.1002/advs.202407370. Online ahead of print.

Authors

Yu Gan^{1

2}, Qian Hao^{1

2}, Tao Han³, Jing Tong^{1

2}, Qingya Yan³, Hongguang Zhong^{4

5}, Bo Gao⁶, Yanan Li⁶, Zhisheng Xuan⁶, Pengfei Li⁷, Litong Yao⁸, Yingying Xu⁸, Yi-Zhou Jiang^{2

9}, Zhi-Ming Shao^{2

9}, Jun Deng^{4

5}, Jiaxiang Chen¹⁰, Xiang Zhou^{1

2

9

11}

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
³ Institutes of Health Central Plains, Xinxiang Key laboratory for Molecular Oncology, Xinxiang Medical University, Xinxiang, Henan, 453003, P. R. China.
⁴ Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, P. R. China.
⁵ Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi, 330006, P. R. China.
⁶ Umibio Co. Ltd., Shanghai, 201210, P. R. China.
⁷ Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, 712046, P. R. China.
⁸ Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China.
⁹ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China.
¹⁰ Department of Physiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, P. R. China.
¹¹ Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.

PMID: 39475053
DOI: 10.1002/advs.202407370

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.

Keywords: BRIX1; engineered exosomes; nucleolar stress; p53; ribosome biogenesis; targeted therapy.

Abstract

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