Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis
© 2021. The Author(s)..
Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular mechanisms is pivotal. Here, we find SIRT7 decline markedly attenuates the anti-tumor effect of IF. Mechanistically, AMP-activated protein kinase (AMPK) phosphorylating SIRT7 at T263 triggers further phosphorylation at T255/S259 by glycogen synthase kinase 3β (GSK3β), which stabilizes SIRT7 by decoupling E3 ligase UBR5. SIRT7 hyperphosphorylation achieves anti-tumor activity by disrupting the SKP2-SCF E3 ligase, thus preventing SKP2-mediated K63-linked AKT polyubiquitination and subsequent activation. In contrast, GSK3β-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3β, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3β-SIRT7 axis via ERK2, thus activating AKT and ensuring survival. Notably, Trametinib, an FDA-approved MEK inhibitor, enhances the efficacy of combination therapy with doxorubicin and IF. Overall, we have revealed the GSK3β-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Nature communications - 12(2021), 1 vom: 25. Aug., Seite 5058 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tang, Xiaolong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.09.2021 Date Revised 04.12.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-021-25274-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329769650 |
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| 100 | 1 | |a Tang, Xiaolong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis |
| 264 | 1 | |c 2021 | |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular mechanisms is pivotal. Here, we find SIRT7 decline markedly attenuates the anti-tumor effect of IF. Mechanistically, AMP-activated protein kinase (AMPK) phosphorylating SIRT7 at T263 triggers further phosphorylation at T255/S259 by glycogen synthase kinase 3β (GSK3β), which stabilizes SIRT7 by decoupling E3 ligase UBR5. SIRT7 hyperphosphorylation achieves anti-tumor activity by disrupting the SKP2-SCF E3 ligase, thus preventing SKP2-mediated K63-linked AKT polyubiquitination and subsequent activation. In contrast, GSK3β-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3β, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3β-SIRT7 axis via ERK2, thus activating AKT and ensuring survival. Notably, Trametinib, an FDA-approved MEK inhibitor, enhances the efficacy of combination therapy with doxorubicin and IF. Overall, we have revealed the GSK3β-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy | ||
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| 700 | 1 | |a Shi, Lei |e verfasserin |4 aut | |
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| 700 | 1 | |a Qian, Minxian |e verfasserin |4 aut | |
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| 700 | 1 | |a Li, Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Baohua |e verfasserin |4 aut | |
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