Sorcin promotes migration and invasion in cancer by regulating the EGF-dependent EGFR signaling pathways

Abstract

Abstract 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 internalization and 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 an important mechanism that links calcium homeostasis to EGFR signaling in cancer. Sorcin and EGFR overexpression are significantly correlated in cancer patients. Sorcin directly binds EGFR in a calcium-dependent fashion and regulates calcium (dys)homeostasis linked to EGF-dependent EGFR signaling. Sorcin controls EGFR signaling, increases its recycling, activates the PI3K/AKT signaling cascade, and controls the RAS/ERK cascade, participating in the regulation of cellular migration and invasion. Sorcin expression leads to increased cell migration, invasion and EMT, via PI3K/AKT signaling; Sorcin silencing reverses these cancer features, synergistically with EGFR inhibitors.