MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis
In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in tu...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/19/4903 |
| _version_ | 1797516747857723392 |
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| author | Silvia Pietrobono Lorenzo Franci Francesco Imperatore Cristina Zanini Barbara Stecca Mario Chiariello |
| author_facet | Silvia Pietrobono Lorenzo Franci Francesco Imperatore Cristina Zanini Barbara Stecca Mario Chiariello |
| author_sort | Silvia Pietrobono |
| collection | DOAJ |
| description | In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative “smart” therapies in medulloblastomas. |
| first_indexed | 2024-03-10T07:05:11Z |
| format | Article |
| id | doaj.art-ce9f891b86cc4a0b86ccc1c2e6dfc3ce |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T07:05:11Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ce9f891b86cc4a0b86ccc1c2e6dfc3ce2023-11-22T15:54:03ZengMDPI AGCancers2072-66942021-09-011319490310.3390/cancers13194903MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary CiliogenesisSilvia Pietrobono0Lorenzo Franci1Francesco Imperatore2Cristina Zanini3Barbara Stecca4Mario Chiariello5Core Research Laboratory—Firenze, Institute for Cancer Research and Prevention (ISPRO), 50139 Firenze, ItalyCore Research Laboratory—Siena, Institute for Cancer Research and Prevention (ISPRO), 53100 Siena, ItalyCore Research Laboratory—Siena, Institute for Cancer Research and Prevention (ISPRO), 53100 Siena, ItalyMolecular Biotechnology Center, BioAir S.p.A Research Laboratory, University of Turin, 10126 Torino, ItalyCore Research Laboratory—Firenze, Institute for Cancer Research and Prevention (ISPRO), 50139 Firenze, ItalyCore Research Laboratory—Siena, Institute for Cancer Research and Prevention (ISPRO), 53100 Siena, ItalyIn medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative “smart” therapies in medulloblastomas.https://www.mdpi.com/2072-6694/13/19/4903MAP Kinasesprimary ciliacancer stem cellsmedullo-spheresGLI1 |
| spellingShingle | Silvia Pietrobono Lorenzo Franci Francesco Imperatore Cristina Zanini Barbara Stecca Mario Chiariello MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis Cancers MAP Kinases primary cilia cancer stem cells medullo-spheres GLI1 |
| title | MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis |
| title_full | MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis |
| title_fullStr | MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis |
| title_full_unstemmed | MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis |
| title_short | MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis |
| title_sort | mapk15 controls hedgehog signaling in medulloblastoma cells by regulating primary ciliogenesis |
| topic | MAP Kinases primary cilia cancer stem cells medullo-spheres GLI1 |
| url | https://www.mdpi.com/2072-6694/13/19/4903 |
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