Gan Yu, Hao Qian, Han Tao, Tong Jing, Yan Qingya, Zhong Hongguang, Gao Bo, Li Yanan, Xuan Zhisheng, Li Pengfei, Yao Litong, Xu Yingying, Jiang Yi-Zhou, Shao Zhi-Ming, Deng Jun, Chen Jiaxiang, Zhou Xiang
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
Adv Sci (Weinh). 2024 Dec;11(47):e2407370. doi: 10.1002/advs.202407370. Epub 2024 Oct 30.
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.
核糖体生物合成增强与癌症的快速生长和进展相关。对核糖体生物合成的靶向阻断会诱导核仁应激，这优先导致恶性细胞的清除。在本研究中，据报道核仁蛋白BRIX1是核糖体生物合成与p53激活之间稳态的关键调节因子。BRIX1通过支持PeBoW复合物的形成促进前体rRNA的加工。此外，BRIX1通过损害MDM2与核糖体蛋白RPL5和RPL11之间的相互作用来阻止核仁应激诱导的p53激活，从而引发癌细胞对化疗的抗性。相反，BRIX1的缺失诱导核仁应激，进而通过RPL5和RPL11激活p53，从而抑制肿瘤生长。此外，开发了工程化外泌体，其表面用肿瘤归巢肽iRGD修饰，并装载有BRIX1特异性的siRNA，用于癌症治疗。iRGD-Exo-siBRIX1在体内显著抑制结直肠癌的生长并增强5-氟尿嘧啶化疗的疗效。总体而言，该研究揭示BRIX1作为一种癌蛋白促进rRNA合成并抑制p53活性，并且还表明通过工程化外泌体靶向抑制BRIX1可能是一种有效的癌症治疗方法。
