Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells
Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic canc...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1476 |
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| author | Mingtian Che Soo-Mi Kweon Jia-Ling Teo Yate-Ching Yuan Laleh G. Melstrom Richard T. Waldron Aurelia Lugea Raul A. Urrutia Stephen J. Pandol Keane K. Y. Lai |
| author_facet | Mingtian Che Soo-Mi Kweon Jia-Ling Teo Yate-Ching Yuan Laleh G. Melstrom Richard T. Waldron Aurelia Lugea Raul A. Urrutia Stephen J. Pandol Keane K. Y. Lai |
| author_sort | Mingtian Che |
| collection | DOAJ |
| description | Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. Methods: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation. Results: We report for the first time that CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; additionally, CBP/β-catenin antagonism also suppresses PSC-induced migration of cancer cells. Conclusion: CBP/β-catenin antagonism represents a novel therapeutic strategy for suppressing PSC activation and may be effective at countering PSC promotion of pancreatic cancer. |
| first_indexed | 2024-03-10T19:22:15Z |
| format | Article |
| id | doaj.art-e21c19489cdf434690ea7f856d433433 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:22:15Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e21c19489cdf434690ea7f856d4334332023-11-20T02:56:33ZengMDPI AGCancers2072-66942020-06-01126147610.3390/cancers12061476Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate CellsMingtian Che0Soo-Mi Kweon1Jia-Ling Teo2Yate-Ching Yuan3Laleh G. Melstrom4Richard T. Waldron5Aurelia Lugea6Raul A. Urrutia7Stephen J. Pandol8Keane K. Y. Lai9Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USAPancreatic Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USAPancreatic Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USADepartment of Surgery and the Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USAPancreatic Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USADepartment of Pathology, City of Hope National Medical Center, and Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USABackground: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. Methods: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation. Results: We report for the first time that CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; additionally, CBP/β-catenin antagonism also suppresses PSC-induced migration of cancer cells. Conclusion: CBP/β-catenin antagonism represents a novel therapeutic strategy for suppressing PSC activation and may be effective at countering PSC promotion of pancreatic cancer.https://www.mdpi.com/2072-6694/12/6/1476pancreatic cancerpancreatic stellate cellsWnt signalingCBPp300pancreatitis |
| spellingShingle | Mingtian Che Soo-Mi Kweon Jia-Ling Teo Yate-Ching Yuan Laleh G. Melstrom Richard T. Waldron Aurelia Lugea Raul A. Urrutia Stephen J. Pandol Keane K. Y. Lai Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells Cancers pancreatic cancer pancreatic stellate cells Wnt signaling CBP p300 pancreatitis |
| title | Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells |
| title_full | Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells |
| title_fullStr | Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells |
| title_full_unstemmed | Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells |
| title_short | Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells |
| title_sort | targeting the cbp β catenin interaction to suppress activation of cancer promoting pancreatic stellate cells |
| topic | pancreatic cancer pancreatic stellate cells Wnt signaling CBP p300 pancreatitis |
| url | https://www.mdpi.com/2072-6694/12/6/1476 |
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