c-Src activation promotes nasopharyngeal carcinoma metastasis by inducing the epithelial-mesenchymal transition via PI3K/Akt signaling pathway: a new and promising target for NPC

Abstract

Aberrant activation of cellular Src (c-Src), a non-receptor tyrosine kinase, could promote cancer progression through activating its downstream signaling pathways. However, the roles of c-Src and phosphorylated-Src (p-Src) in nasopharyngeal carcinoma (NPC) progression are rarely investigated. Herein, we have identified high c-Src concentrations in the serum of NPC patients with distant metastasis using high-throughput protein microarrays. Levels of c-Src in serum and p-Src in human primary NPC samples were unfavorable independent prognostic factors for cancer-specific survival, disease-free survival, and distant metastasis-free survival. Depletion or inactivation of c-Src in NPC cells using sgRNA with CRISPR/Cas9 system or PP2 decreased cell viability, colony formation, migration and invasion in vitro and metastasis in vivo. In contrast, these malignancies could be up-regulated by overexpressed c-Src in a NPC cell line with low-metastasis potential. Furthermore, p-Src was involved in promoting NPC cell metastasis by inducing the epithelial-mesenchymal transition (EMT) process via activating the PI3K/Akt pathway and cytoskeleton remodeling. The p-Src-induced EMT process could be retarded by PP2, which mediated by down-regulating the PI3K/Akt pathway. In conclusion, elevated levels of c-Src in serum and p-Src in primary NPC tissue correlated with poor outcomes of NPC patients. And aberrant activation of c-Src facilitated NPC cells with malignant potential, especially metastasis ability, which mediated by the PI3K/Akt pathway activation and sequentially induced the EMT process. These findings unveiled a promising approach for targeted therapy of advanced NPC.

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

“…There are more than 10 co-chaperones of HSP90, which individually carry out distinct cooperative roles with HSP90 in cells [87]. CDC37 is a definitive kinome chaperone assisting in the folding of protein kinases such as SRC, many receptor tyrosine kinases (RTK), their downstream Ras/Raf/MEK/ERK signaling pathway, and PI3K-AKT signaling pathway, which promote EMT [88][89][90][91]. Among such key kinases, a recent study showed that SRC in endosomal membranes promoted exosome secretion and tumor progression [92].…”

Suppression of STIM1 inhibits the migration and invasion of human prostate cancer cells and is associated with PI3K/Akt signaling inactivation

“…PI3K/Akt is over-activated in a various types of cancer, and is associated with progression of malignancy and, in particular, metastasis. Inhibition of the PI3K/Akt pathway was revealed to suppress invasion and migration in a variety of cancer models and was considered to be a potential therapeutic approach to combat cancer metastases ( 38 – 40 ).…”

CDC37 and HSP90 are Essential for Stressome Release and Tumor Progression in Resistant Prostate Cancer

“…There are more than ten co-chaperones of HSP90, which individually carry out distinct cooperative roles with HSP90 in cells [82]. CDC37 is a definitive kinome chaperone assisting in the folding of protein kinases such as SRC, many receptor tyrosine kinases (RTK), their downstream Ras/Raf/MEK/ERK signaling pathway, and PI3K-AKT signaling pathway, which promote EMT [83][84][85][86]. Among such key kinases, a recent study showed that SRC in endosomal membranes promoted exosome secretion and tumor progression [87].…”