Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly
Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Science translational medicine - 16(2024), 739 vom: 20. März, Seite eadg5553 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yin, Jianxing [VerfasserIn] |
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| Links: |
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| Themen: |
70FD1KFU70 |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 22.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.adg5553 |
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| funding: |
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NLM36997073X |
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| 520 | |a Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC | ||
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| 700 | 1 | |a Ge, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Fangshu |e verfasserin |4 aut | |
| 700 | 1 | |a He, Liuguijie |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Keying |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Zhumei |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Zehe |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Junxia |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiefeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Ningwei |e verfasserin |4 aut | |
| 700 | 1 | |a Shu, Chuanjun |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qianghu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qigang |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Yuandong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wentao |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Rich, Jeremy N |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiuxing |e verfasserin |4 aut | |
| 700 | 1 | |a You, Yongping |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Xu |e verfasserin |4 aut | |
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