Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation
Abstract The extracellular matrix plays a key role in cancer progression. Hyaluronan, the main glycosaminoglycan of the extracellular matrix, has been related to several tumor processes. Hyaluronan acts through the interaction with cell membrane receptors as CD44 and RHAMM and triggers signaling pat...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-10-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-021-00672-0 |
| _version_ | 1818399273349283840 |
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| author | Matías Arturo Pibuel Daniela Poodts Mariángeles Díaz Yamila Azul Molinari Paula Gabriela Franco Silvia Elvira Hajos Silvina Laura Lompardía |
| author_facet | Matías Arturo Pibuel Daniela Poodts Mariángeles Díaz Yamila Azul Molinari Paula Gabriela Franco Silvia Elvira Hajos Silvina Laura Lompardía |
| author_sort | Matías Arturo Pibuel |
| collection | DOAJ |
| description | Abstract The extracellular matrix plays a key role in cancer progression. Hyaluronan, the main glycosaminoglycan of the extracellular matrix, has been related to several tumor processes. Hyaluronan acts through the interaction with cell membrane receptors as CD44 and RHAMM and triggers signaling pathways as MEK/ERK. 4-methylumbelliferone (4MU), a well-known hyaluronan synthesis inhibitor, is a promising alternative for cancer therapy. 4MU is a coumarin derivative without adverse effects that has been studied in several tumors. However, little is known about its use in glioblastoma (GBM), the most malignant primary brain tumor in adults. Glioblastoma is characterized by fast growth, migration and tissue invasiveness, and a poor median survival of the patients after treatment. Several reports linked glioblastoma progression with HA levels and even with CD44 and RHAMM expression, as well as MEK/ERK activation. Previously, we showed on a murine GBM cell line that HA enhances GBM migration, while 4MU markedly inhibits it. In this work we showed for the first time, that 4MU decreases cell migration and induces senescence in U251 and LN229 human GBM cell lines. Furthermore, we observed that HA promotes GBM cell migration on both cell lines and that such effects depend on CD44 and RHAMM, as well as MEK/ERK signaling pathway. Interestingly, we observed that the exogenous HA failed to counteract the effects of 4MU, indicating that 4MU effects are independent of HA synthesis inhibition. We found that 4MU decreases total CD44 and RHAMM membrane expression, which could explain the effect of 4MU on cell migration. Furthermore, we observed that 4MU increases the levels of RHAMM inside the cell while decreases the nucleus/cytoplasm relation of p-ERK, associated with 4MU effects on cell proliferation and senescence induction. Overall, 4MU should be considered as a promising therapeutic alternative to improve the outcome of patients with GBM. |
| first_indexed | 2024-12-14T07:18:03Z |
| format | Article |
| id | doaj.art-01fb9a0958ba43b6b1a4cfa7f40656f7 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-14T07:18:03Z |
| publishDate | 2021-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-01fb9a0958ba43b6b1a4cfa7f40656f72022-12-21T23:11:40ZengNature Publishing GroupCell Death Discovery2058-77162021-10-017111410.1038/s41420-021-00672-0Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulationMatías Arturo Pibuel0Daniela Poodts1Mariángeles Díaz2Yamila Azul Molinari3Paula Gabriela Franco4Silvia Elvira Hajos5Silvina Laura Lompardía6Instituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET; Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresInstituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET; Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresInstituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET, Universidad de Buenos AiresInstituto de Química y Fisicoquímica Biológicas (IQUIFIB)-CONICET; Departamento de Química Biológica, Cátedra de Química Biológica Patológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresInstituto de Química y Fisicoquímica Biológicas (IQUIFIB)-CONICET; Departamento de Química Biológica, Cátedra de Química Biológica Patológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresInstituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET; Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresInstituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET; Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresAbstract The extracellular matrix plays a key role in cancer progression. Hyaluronan, the main glycosaminoglycan of the extracellular matrix, has been related to several tumor processes. Hyaluronan acts through the interaction with cell membrane receptors as CD44 and RHAMM and triggers signaling pathways as MEK/ERK. 4-methylumbelliferone (4MU), a well-known hyaluronan synthesis inhibitor, is a promising alternative for cancer therapy. 4MU is a coumarin derivative without adverse effects that has been studied in several tumors. However, little is known about its use in glioblastoma (GBM), the most malignant primary brain tumor in adults. Glioblastoma is characterized by fast growth, migration and tissue invasiveness, and a poor median survival of the patients after treatment. Several reports linked glioblastoma progression with HA levels and even with CD44 and RHAMM expression, as well as MEK/ERK activation. Previously, we showed on a murine GBM cell line that HA enhances GBM migration, while 4MU markedly inhibits it. In this work we showed for the first time, that 4MU decreases cell migration and induces senescence in U251 and LN229 human GBM cell lines. Furthermore, we observed that HA promotes GBM cell migration on both cell lines and that such effects depend on CD44 and RHAMM, as well as MEK/ERK signaling pathway. Interestingly, we observed that the exogenous HA failed to counteract the effects of 4MU, indicating that 4MU effects are independent of HA synthesis inhibition. We found that 4MU decreases total CD44 and RHAMM membrane expression, which could explain the effect of 4MU on cell migration. Furthermore, we observed that 4MU increases the levels of RHAMM inside the cell while decreases the nucleus/cytoplasm relation of p-ERK, associated with 4MU effects on cell proliferation and senescence induction. Overall, 4MU should be considered as a promising therapeutic alternative to improve the outcome of patients with GBM.https://doi.org/10.1038/s41420-021-00672-0 |
| spellingShingle | Matías Arturo Pibuel Daniela Poodts Mariángeles Díaz Yamila Azul Molinari Paula Gabriela Franco Silvia Elvira Hajos Silvina Laura Lompardía Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation Cell Death Discovery |
| title | Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation |
| title_full | Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation |
| title_fullStr | Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation |
| title_full_unstemmed | Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation |
| title_short | Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation |
| title_sort | antitumor effect of 4mu on glioblastoma cells is mediated by senescence induction and cd44 rhamm and p erk modulation |
| url | https://doi.org/10.1038/s41420-021-00672-0 |
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