Section of Histology and Medical Embryology, Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Via A. Scarpa, 14-16, 00161, Rome, Italy.
Institute of Molecular Biology and Pathology, Italian National Research Council, IBPM-CNR, P.le A. Moro 5, 00185, Rome, Italy.
Cell Mol Life Sci. 2023 Jul 13;80(8):202. doi: 10.1007/s00018-023-04850-4.
The epidermal growth factor receptor (EGFR) is one of the main tumor drivers and is an important therapeutic target for many cancers. Calcium is important in EGFR signaling pathways. Sorcin is one of the most important calcium sensor proteins, overexpressed in many tumors, that promotes cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, malignant progression and resistance to chemotherapeutic drugs. The present work elucidates a functional mechanism that links calcium homeostasis to EGFR signaling in cancer. Sorcin and EGFR expression are significantly correlated and associated with reduced overall survival in cancer patients. Mechanistically, Sorcin directly binds EGFR protein in a calcium-dependent fashion and regulates calcium (dys)homeostasis linked to EGF-dependent EGFR signaling. Moreover, Sorcin controls EGFR proteostasis and signaling and increases its phosphorylation, leading to increased EGF-dependent migration and invasion. Of note, silencing of Sorcin cooperates with EGFR inhibitors in the regulation of migration, highlighting calcium signaling pathway as an exploitable target to enhance the effectiveness of EGFR-targeting therapies.
表皮生长因子受体（EGFR）是主要的肿瘤驱动因子之一，是许多癌症的重要治疗靶点。钙在 EGFR 信号通路中起着重要作用。钙结合蛋白 Sorcin 是最重要的钙传感器蛋白之一，在许多肿瘤中过度表达，可促进细胞增殖、迁移、侵袭、上皮-间充质转化、恶性进展和对化疗药物的耐药性。本研究阐明了钙稳态与癌症中 EGFR 信号之间的功能机制。Sorcin 和 EGFR 的表达呈显著相关性，并与癌症患者的总生存率降低相关。从机制上讲，Sorcin 以钙依赖性的方式直接与 EGFR 蛋白结合，并调节与 EGF 依赖性 EGFR 信号相关的钙（失调）稳态。此外，Sorcin 控制 EGFR 蛋白稳态和信号，增加其磷酸化，从而导致 EGF 依赖性迁移和侵袭增加。值得注意的是，沉默 Sorcin 与 EGFR 抑制剂协同调节迁移，凸显了钙信号通路作为一个可利用的靶点，以增强 EGFR 靶向治疗的有效性。
