Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer
Bladder cancer is one of the most common and aggressive cancers and, regardless of the treatment, often recurs and metastasizes. Thus, a better understanding of the mechanisms regulating urothelial tumorigenesis is critical for the design and implementation of rational therapeutic strategies. We pre...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-05-01
|
| Series: | Matrix Biology Plus |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S259002852030003X |
| _version_ | 1818248495009628160 |
|---|---|
| author | Simone Buraschi Alaide Morcavallo Thomas Neill Manuela Stefanello Chiara Palladino Shi-Qiong Xu Antonino Belfiore Renato V. Iozzo Andrea Morrione |
| author_facet | Simone Buraschi Alaide Morcavallo Thomas Neill Manuela Stefanello Chiara Palladino Shi-Qiong Xu Antonino Belfiore Renato V. Iozzo Andrea Morrione |
| author_sort | Simone Buraschi |
| collection | DOAJ |
| description | Bladder cancer is one of the most common and aggressive cancers and, regardless of the treatment, often recurs and metastasizes. Thus, a better understanding of the mechanisms regulating urothelial tumorigenesis is critical for the design and implementation of rational therapeutic strategies. We previously discovered that the IGF-IR axis is critical for bladder cancer cell motility and invasion, suggesting a possible role in bladder cancer progression. However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibited anchorage-independent growth. Significantly, metastatic bladder cancer cells have decreased IGF-IR levels but overexpressed the insulin receptor isoform A (IR-A), suggesting that the latter may play a more prevalent role than the IGF-IR in bladder tumor progression. The collagen receptor DDR1 cross-talks with both the IGF-IR and IR in breast cancer, and previous data suggest a role of DDR1 in bladder cancer. Here, we show that DDR1 is expressed in invasive and metastatic, but not in papillary, non-invasive bladder cancer cells. DDR1 is phosphorylated upon stimulation with IGF-I, IGF-II, and insulin, co-precipitates with the IGF-IR, and the IR-A and transient DDR1 depletion severely inhibits IGF-I-induced motility. We further demonstrate that DDR1 interacts with Pyk2 and non-muscle myosin IIA in ligands-dependent fashion, suggesting that it may link the IGF-IR and IR-A to the regulation of F-actin cytoskeleton dynamics. Similarly to the IGF-IR, DDR1 is upregulated in bladder cancer tissues compared to healthy tissue controls. Thus, our findings provide the first characterization of the molecular cross-talk between DDR1 and the IGF-I system and could lead to the identification of novel targets for therapeutic intervention in bladder cancer. Moreover, the expression profiles of IGF-IR, IR-A, DDR1, and downstream effectors could serve as a novel biomarker signature with diagnostic and prognostic significance. |
| first_indexed | 2024-12-12T15:21:30Z |
| format | Article |
| id | doaj.art-cb38a426bf8b46ac96fb4f0ebad3ce01 |
| institution | Directory Open Access Journal |
| issn | 2590-0285 |
| language | English |
| last_indexed | 2024-12-12T15:21:30Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Matrix Biology Plus |
| spelling | doaj.art-cb38a426bf8b46ac96fb4f0ebad3ce012022-12-22T00:20:22ZengElsevierMatrix Biology Plus2590-02852020-05-016100022Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancerSimone Buraschi0Alaide Morcavallo1Thomas Neill2Manuela Stefanello3Chiara Palladino4Shi-Qiong Xu5Antonino Belfiore6Renato V. Iozzo7Andrea Morrione8Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USAEndocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, ItalyDepartment of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Corresponding author.Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA; Correspondence to: A.Morrione, Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USABladder cancer is one of the most common and aggressive cancers and, regardless of the treatment, often recurs and metastasizes. Thus, a better understanding of the mechanisms regulating urothelial tumorigenesis is critical for the design and implementation of rational therapeutic strategies. We previously discovered that the IGF-IR axis is critical for bladder cancer cell motility and invasion, suggesting a possible role in bladder cancer progression. However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibited anchorage-independent growth. Significantly, metastatic bladder cancer cells have decreased IGF-IR levels but overexpressed the insulin receptor isoform A (IR-A), suggesting that the latter may play a more prevalent role than the IGF-IR in bladder tumor progression. The collagen receptor DDR1 cross-talks with both the IGF-IR and IR in breast cancer, and previous data suggest a role of DDR1 in bladder cancer. Here, we show that DDR1 is expressed in invasive and metastatic, but not in papillary, non-invasive bladder cancer cells. DDR1 is phosphorylated upon stimulation with IGF-I, IGF-II, and insulin, co-precipitates with the IGF-IR, and the IR-A and transient DDR1 depletion severely inhibits IGF-I-induced motility. We further demonstrate that DDR1 interacts with Pyk2 and non-muscle myosin IIA in ligands-dependent fashion, suggesting that it may link the IGF-IR and IR-A to the regulation of F-actin cytoskeleton dynamics. Similarly to the IGF-IR, DDR1 is upregulated in bladder cancer tissues compared to healthy tissue controls. Thus, our findings provide the first characterization of the molecular cross-talk between DDR1 and the IGF-I system and could lead to the identification of novel targets for therapeutic intervention in bladder cancer. Moreover, the expression profiles of IGF-IR, IR-A, DDR1, and downstream effectors could serve as a novel biomarker signature with diagnostic and prognostic significance.http://www.sciencedirect.com/science/article/pii/S259002852030003XBladder cancerDDR1IGF systemMotilityIGF-IRIR |
| spellingShingle | Simone Buraschi Alaide Morcavallo Thomas Neill Manuela Stefanello Chiara Palladino Shi-Qiong Xu Antonino Belfiore Renato V. Iozzo Andrea Morrione Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer Matrix Biology Plus Bladder cancer DDR1 IGF system Motility IGF-IR IR |
| title | Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer |
| title_full | Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer |
| title_fullStr | Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer |
| title_full_unstemmed | Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer |
| title_short | Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer |
| title_sort | discoidin domain receptor 1 functionally interacts with the igf i system in bladder cancer |
| topic | Bladder cancer DDR1 IGF system Motility IGF-IR IR |
| url | http://www.sciencedirect.com/science/article/pii/S259002852030003X |
| work_keys_str_mv | AT simoneburaschi discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT alaidemorcavallo discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT thomasneill discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT manuelastefanello discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT chiarapalladino discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT shiqiongxu discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT antoninobelfiore discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT renatoviozzo discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer AT andreamorrione discoidindomainreceptor1functionallyinteractswiththeigfisysteminbladdercancer |