The Oncolytic Avian Reovirus p17 Protein Inhibits Invadopodia Formation in Murine Melanoma Cancer Cells by Suppressing the FAK/Src Pathway and the Formation of theTKs5/NCK1 Complex

• Published in: Viruses Vol. 16; no. 7; p. 1153
• Main Authors: Hsu, Chao-Yu, Li, Jyun-Yi, Yang, En-Ying, Liao, Tsai-Ling, Wen, Hsiao-Wei, Tsai, Pei-Chien, Ju, Tz-Chuen, Lye, Lon-Fye, Nielsen, Brent L., Liu, Hung-Jen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2024
• Subjects: Adaptor proteins; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Angiogenesis; Animals; Antibodies; Avian orthoreovirus; avian reoviruses; Breast cancer; Cancer; Cancer cells; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; cell lines; Cell migration; Cell Movement; Cellular signal transduction; Efficiency; FAK/Src; Focal adhesion kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gelatinase B; Genomes; Health aspects; Kinases; Matrix metalloproteinase; Medical research; Medicine, Experimental; Melanoma; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; metalloproteinases; Metastasis; Mice; mutants; neoplasm cells; non-specific protein-tyrosine kinase; Oncolysis; Oncolytic Viruses - genetics; Oncolytic Viruses - physiology; Orthoreovirus, Avian - genetics; Orthoreovirus, Avian - physiology; p17; p17 Protein; p53 Protein; p53/PTEN; Phosphotransferases; Physiological aspects; Plasmids; Podosomes - metabolism; Proteins; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Rab40b; Reoviruses; Signal Transduction; Src protein; src-Family Kinases - genetics; src-Family Kinases - metabolism; TKs5/NCK1 complex; transcription (genetics); Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; tyrosine; Viral proteins; Viral Proteins - genetics; Viral Proteins - metabolism; Wound healing; Taiwan; United States > US; Rab40b; invadopodia; FAK/Src; p17; TKs5/NCK1 complex; MMP9; avian reoviruses; p53/PTEN
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16071153

To explore whether the p17 protein of oncolytic avian reovirus (ARV) mediates cell migration and invadopodia formation, we applied several molecular biological approaches for studying the involved cellular factors and signal pathways. We found that ARV p17 activates the p53/phosphatase and tensin homolog (PTEN) pathway to suppress the focal adhesion kinase (FAK)/Src signaling and downstream signal molecules, thus inhibiting cell migration and the formation of invadopodia in murine melanoma cancer cell line (B16-F10). Importantly, p17-induced formation of invadopodia could be reversed in cells transfected with the mutant PTENC124A. p17 protein was found to significantly reduce the expression levels of tyrosine kinase substrate 5 (TKs5), Rab40b, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), and matrix metalloproteinases (MMP9), suggesting that TKs5 and Rab40b were transcriptionally downregulated by p17. Furthermore, we found that p17 suppresses the formation of the TKs5/NCK1 complex. Coexpression of TKs5 and Rab40b in B16-F10 cancer cells reversed p17-modulated suppression of the formation of invadopodia. This work provides new insights into p17-modulated suppression of invadopodia formation by activating the p53/PTEN pathway, suppressing the FAK/Src pathway, and inhibiting the formation of the TKs5/NCK1 complex.