Aurora-A drives sorafenib resistance by scaffolding stress granule assembly via phase separation
Abstract
The mitotic kinase Aurora-A is frequently overexpressed in cancers and contributes to tumor progression and therapy resistance, yet the mechanisms underlying its role in drug resistance remain unclear. Here, we show that sorafenib treatment triggers Aurora-A phase separation, leading to its recruitment into stress granules (SGs), membraneless organelles that promote cancer cell survival. Aurora-A facilitates robust SGs assembly, thereby conferring sorafenib resistance. Mechanistically, upon sorafenib-induced SGs formation, Aurora-A binds RNA via positively charged lysine/arginine residues within its intrinsically disordered region (IDR). Mutating these K/R residues with IDR of Aurora-A disrupts its RNA binding, impairs SGs assembly, and resensitizes cancer cells to sorafenib. Together, our work identifies Aurora-A as a kinase-activity-independent, RNA-binding scaffold essential for stress-adaptive biomolecular condensation, revealing a druggable phase-separation axis distinct from canonical Aurora-A kinase signaling.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Lingyu Kong
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China
Fumei Zhong
Ministry of Education (MOE) Key Laboratory for Cellular Dynamics and Membraneless Organelle, Division of Life Sciences and Medicine, University of Science and Technology of China
Fazhi Yu
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China
Ting Wang
Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Gang Wang
Yu Bai
Han Xia
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China
Zihang Pan
Mingxue Liu
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China
Yan Zhang
Rui Feng
Jiahai Zhang
Ministry of Education (MOE) Key Laboratory for Cellular Dynamics and Membraneless Organelle, Division of Life Sciences and Medicine, University of Science and Technology of China
Yingying Du
Department of Oncology, the First Affiliated Hospital of Anhui Medical University
Kaiguang Zhang
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China
Jing Guo
Ke Ruan
Ministry of Education (MOE) Key Laboratory for Cellular Dynamics and Membraneless Organelle, Division of Life Sciences and Medicine, University of Science and Technology of China
Zhenye Yang
Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China