Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine
Abstract Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutation in the neurofibromin 1 (NF1) gene. Its hallmarks are cutaneous findings including neurofibromas, benign peripheral nerve sheath tumors. We analyzed the collagen and matrix metalloproteinase 1 (MMP1) expres...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03802-9 |
| _version_ | 1818455014831554560 |
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| author | Gaku Tsuji Ayako Takai-Yumine Takahiro Kato Masutaka Furue |
| author_facet | Gaku Tsuji Ayako Takai-Yumine Takahiro Kato Masutaka Furue |
| author_sort | Gaku Tsuji |
| collection | DOAJ |
| description | Abstract Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutation in the neurofibromin 1 (NF1) gene. Its hallmarks are cutaneous findings including neurofibromas, benign peripheral nerve sheath tumors. We analyzed the collagen and matrix metalloproteinase 1 (MMP1) expression in Neurofibromatosis 1 cutaneous neurofibroma and found excessive expression of collagen and reduced expression of MMP1. To identify new therapeutic drugs for neurofibroma, we analyzed phosphorylation of components of the Ras pathway, which underlies NF1 regulation, and applied treatments to block this pathway (PD184352, U0126, and rapamycin) and lysosomal processes (chloroquine (CQ), hydroxychloroquine (HCQ), and bafilomycin A (BafA)) in cultured Neurofibromatosis 1 fibroblasts. We found that downregulation of the MMP1 protein was a key abnormal feature in the neurofibromatosis 1 fibroblasts and that the decreased MMP1 was restored by the lysosomal blockers CQ and HCQ, but not by the blockers of the Ras pathway. Moreover, the MMP1-upregulating activity of those lysosomal blockers was dependent on aryl hydrocarbon receptor (AHR) activation and ERK phosphorylation. Our findings suggest that lysosomal blockers are potential candidates for the treatment of Neurofibromatosis 1 neurofibroma. |
| first_indexed | 2024-12-14T22:04:03Z |
| format | Article |
| id | doaj.art-533521085f8748f2aabc7cacfec5f125 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T22:04:03Z |
| publishDate | 2021-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-533521085f8748f2aabc7cacfec5f1252022-12-21T22:45:54ZengNature Publishing GroupCell Death and Disease2041-48892021-05-0112611110.1038/s41419-021-03802-9Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquineGaku Tsuji0Ayako Takai-Yumine1Takahiro Kato2Masutaka Furue3Department of Dermatology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Dermatology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Dermatology, Graduate School of Medical Sciences, Kyushu UniversityAbstract Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutation in the neurofibromin 1 (NF1) gene. Its hallmarks are cutaneous findings including neurofibromas, benign peripheral nerve sheath tumors. We analyzed the collagen and matrix metalloproteinase 1 (MMP1) expression in Neurofibromatosis 1 cutaneous neurofibroma and found excessive expression of collagen and reduced expression of MMP1. To identify new therapeutic drugs for neurofibroma, we analyzed phosphorylation of components of the Ras pathway, which underlies NF1 regulation, and applied treatments to block this pathway (PD184352, U0126, and rapamycin) and lysosomal processes (chloroquine (CQ), hydroxychloroquine (HCQ), and bafilomycin A (BafA)) in cultured Neurofibromatosis 1 fibroblasts. We found that downregulation of the MMP1 protein was a key abnormal feature in the neurofibromatosis 1 fibroblasts and that the decreased MMP1 was restored by the lysosomal blockers CQ and HCQ, but not by the blockers of the Ras pathway. Moreover, the MMP1-upregulating activity of those lysosomal blockers was dependent on aryl hydrocarbon receptor (AHR) activation and ERK phosphorylation. Our findings suggest that lysosomal blockers are potential candidates for the treatment of Neurofibromatosis 1 neurofibroma.https://doi.org/10.1038/s41419-021-03802-9 |
| spellingShingle | Gaku Tsuji Ayako Takai-Yumine Takahiro Kato Masutaka Furue Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine Cell Death and Disease |
| title | Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| title_full | Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| title_fullStr | Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| title_full_unstemmed | Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| title_short | Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| title_sort | metalloproteinase 1 downregulation in neurofibromatosis 1 therapeutic potential of antimalarial hydroxychloroquine and chloroquine |
| url | https://doi.org/10.1038/s41419-021-03802-9 |
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