RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions
©2021 American Association for Cancer Research..
Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGFβ signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST.
IMPLICATIONS: This study identifies that a selective RKIP inducer inhibits tumor growth and promotes schwannoma cell differentiation under NF2-deficient conditions by reducing SOX2 and increasing SOX10 expression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Molecular cancer research : MCR - 20(2022), 3 vom: 01. März, Seite 412-424 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cho, Jung-Hyun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.04.2022 Date Revised 31.05.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1541-7786.MCR-21-0373 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM332667235 |
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| 100 | 1 | |a Cho, Jung-Hyun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 27.04.2022 | ||
| 500 | |a Date Revised 31.05.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGFβ signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST | ||
| 520 | |a IMPLICATIONS: This study identifies that a selective RKIP inducer inhibits tumor growth and promotes schwannoma cell differentiation under NF2-deficient conditions by reducing SOX2 and increasing SOX10 expression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Neurofibromin 2 |2 NLM | |
| 650 | 7 | |a PEBP1 protein, human |2 NLM | |
| 650 | 7 | |a Phosphatidylethanolamine Binding Protein |2 NLM | |
| 650 | 7 | |a Raf kinase inhibitory protein, mouse |2 NLM | |
| 650 | 7 | |a SOX2 protein, human |2 NLM | |
| 650 | 7 | |a SOXB1 Transcription Factors |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 700 | 1 | |a Park, Soyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Soyeong |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, So-Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Woo, Tae-Gyun |e verfasserin |4 aut | |
| 700 | 1 | |a Yoon, Min-Ho |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Hyunkee |e verfasserin |4 aut | |
| 700 | 1 | |a Jeong, Myeonggyo |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Yeong Hye |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Heegyu |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Young Taek |e verfasserin |4 aut | |
| 700 | 1 | |a Suh, Young-Ger |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Bae-Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Kwon, Yonghoon |e verfasserin |4 aut | |
| 700 | 1 | |a Yun, Hwayoung |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Bum-Joon |e verfasserin |4 aut | |
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