The oncolytic avian reovirus p17 protein suppresses invadopodia formation via disruption of TKs5 complexes and oncogenic signaling pathways
Avian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essentia...
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| Published in | Frontiers in cellular and infection microbiology Vol. 15; p. 1603124 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Frontiers Media S.A
12.06.2025
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| Abstract | Avian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression.
This study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17.
p17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17's inhibitory effects.
ARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells. |
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| AbstractList | Avian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression.BackgroundAvian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression.This study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17.MethodsThis study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17.p17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17's inhibitory effects.Resultsp17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17's inhibitory effects.ARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells.ConclusionARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells. BackgroundAvian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression.MethodsThis study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17.Resultsp17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17’s inhibitory effects.ConclusionARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells. Avian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression. This study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17. p17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17's inhibitory effects. ARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells. |
| Author | Liu, Hung-Jen Hsu, Chao-Yu Wen, Hsiao-Wei Nielsen, Brent L. Liao, Tsai-Ling Wang, Chi-Young Lye, Lon-Fye Li, Jyun-Yi Huang, Wei-Ru |
| AuthorAffiliation | 7 Department of Veterinary Medicine, National Chung Hsing University , Taichung , Taiwan 3 The iEGG and Animal Biotechnology Center, National Chung Hsing University , Taichung , Taiwan 5 Department of Medical Research, Taichung Veterans General Hospital , Taichung , Taiwan 6 Department of Food Science and Biotechnology, National Chung Hsing University , Taichung , Taiwan 10 Department of Life Sciences, National Chung Hsing University , Taichung , Taiwan 11 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University , Taichung , Taiwan 2 Institute of Molecular Biology, National Chung Hsing University , Taichung , Taiwan 4 Ph.D Program in Translational Medicine, National Chung Hsing University , Taichung , Taiwan 1 Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital , Taichung , Taiwan 9 Department of Microbiology and Molecular Biology, Brigham Young University , Provo, UT , United States 8 Department of Medical Research, Tungs’ Taichung Metr |
| AuthorAffiliation_xml | – name: 6 Department of Food Science and Biotechnology, National Chung Hsing University , Taichung , Taiwan – name: 7 Department of Veterinary Medicine, National Chung Hsing University , Taichung , Taiwan – name: 5 Department of Medical Research, Taichung Veterans General Hospital , Taichung , Taiwan – name: 11 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University , Taichung , Taiwan – name: 8 Department of Medical Research, Tungs’ Taichung MetroHarbor Hospital , Taichung , Taiwan – name: 9 Department of Microbiology and Molecular Biology, Brigham Young University , Provo, UT , United States – name: 10 Department of Life Sciences, National Chung Hsing University , Taichung , Taiwan – name: 3 The iEGG and Animal Biotechnology Center, National Chung Hsing University , Taichung , Taiwan – name: 2 Institute of Molecular Biology, National Chung Hsing University , Taichung , Taiwan – name: 4 Ph.D Program in Translational Medicine, National Chung Hsing University , Taichung , Taiwan – name: 1 Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital , Taichung , Taiwan |
| Author_xml | – sequence: 1 givenname: Chao-Yu surname: Hsu fullname: Hsu, Chao-Yu – sequence: 2 givenname: Jyun-Yi surname: Li fullname: Li, Jyun-Yi – sequence: 3 givenname: Wei-Ru surname: Huang fullname: Huang, Wei-Ru – sequence: 4 givenname: Tsai-Ling surname: Liao fullname: Liao, Tsai-Ling – sequence: 5 givenname: Hsiao-Wei surname: Wen fullname: Wen, Hsiao-Wei – sequence: 6 givenname: Chi-Young surname: Wang fullname: Wang, Chi-Young – sequence: 7 givenname: Lon-Fye surname: Lye fullname: Lye, Lon-Fye – sequence: 8 givenname: Brent L. surname: Nielsen fullname: Nielsen, Brent L. – sequence: 9 givenname: Hung-Jen surname: Liu fullname: Liu, Hung-Jen |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40575485$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2025 Hsu, Li, Huang, Liao, Wen, Wang, Lye, Nielsen and Liu. Copyright © 2025 Hsu, Li, Huang, Liao, Wen, Wang, Lye, Nielsen and Liu 2025 Hsu, Li, Huang, Liao, Wen, Wang, Lye, Nielsen and Liu |
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| Keywords | TKs5-Nck1 complex oncolytic avian reovirus p53-PTEN-FAK-Src invadopodia formation p17 |
| Language | English |
| License | Copyright © 2025 Hsu, Li, Huang, Liao, Wen, Wang, Lye, Nielsen and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Ruixue Wang, Foshan University, China Edited by: Chandrabose Selvaraj, Amet University, India Uksha Saini, Fannin Innovation Studio, United States Richa Arora, Bihar Animal Sciences University, India These authors have contributed equally to this work Yumiko Yamada, Cleveland Clinic, United States |
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| SubjectTerms | A549 Cells Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Cell Line, Tumor Cell Movement - drug effects Cellular and Infection Microbiology HeLa Cells Humans invadopodia formation oncolytic avian reovirus Oncolytic Viruses - genetics Orthoreovirus, Avian - genetics Orthoreovirus, Avian - metabolism p17 p53-PTEN-FAK-Src Podosomes - metabolism Podosomes - virology PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Signal Transduction TKs5-Nck1 complex |
| Title | The oncolytic avian reovirus p17 protein suppresses invadopodia formation via disruption of TKs5 complexes and oncogenic signaling pathways |
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