Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis.
Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis.
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间歇性禁食和 ERK 抑制相结合可通过 GSK3β-SIRT7 轴增强化疗的抗肿瘤作用
DOI：
10.1038/s41467-021-25274-3
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发表时间：
2021-08-25
影响因子：
16.6
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Tang X;Li G;Shi L;Su F;Qian M;Liu Z;Meng Y;Sun S;Li J;Liu B
间歇性禁食（IF）等饮食干预已成为癌症治疗的一种有吸引力的策略;因此，了解潜在的分子机制至关重要。在这里，我们发现SIRT 7的下降显著减弱了IF的抗肿瘤作用。从机制上讲，AMP活化蛋白激酶（AMPK）在T263处磷酸化SIRT 7，触发糖原合成酶激酶3β（GSK 3 β）在T255/S259处进一步磷酸化，后者通过使E3连接酶UBR 5解偶联来稳定SIRT 7。SIRT 7过度磷酸化通过破坏SKP 2-SCF E3连接酶实现抗肿瘤活性，从而阻止SKP 2介导的K63连接的AKT多聚泛素化和随后的活化。相反，GSK 3 β-SIRT 7轴被EGF/ERK 2信号转导抑制，ERK 2使GSK 3 β失活，从而加速SIRT 7降解。不利的是，葡萄糖剥夺或化疗通过ERK 2劫持GSK 3 β-SIRT 7轴，从而激活AKT并确保存活。值得注意的是，曲美替尼是一种FDA批准的MEK抑制剂，可增强多柔比星和IF联合治疗的疗效。总的来说，我们已经揭示了GSK 3 β-SIRT 7轴必须在恶性肿瘤中面对能量和致癌压力时进行微调。间歇性禁食和化疗的结合可以改善对治疗的反应。在这里，作者表明，在间歇性禁食期间需要SIRT 7激活来抑制Akt，并且间歇性禁食和阻断Erk通路的抑制剂的组合可以提高治疗效果。
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. The combination of intermittent fasting and chemotherapy can improve the response to treatment. Here, the authors show that SIRT7 activation is required to inactivate Akt during intermittent fasting and that the combination of intermittent fasting and inhibitors that block the Erk pathway can improve efficacy of treatment.
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影响因子：
16.6
作者：
Han F;Li CF;Cai Z;Zhang X;Jin G;Zhang WN;Xu C;Wang CY;Morrow J;Zhang S;Xu D;Wang G;Lin HK
通讯作者：
Lin HK
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
15.9
作者：
Cipriano, Rocky;Graham, James;Jackson, Mark W.
通讯作者：
Jackson, Mark W.
影响因子：
14.5
作者：
Cai, Zhen;Moten, Asad;Peng, Danni;Hsu, Che-Chia;Pan, Bo-Syong;Manne, Rajeshkumar;Li, Hong-yu;Lin, Hui-Kuan
通讯作者：
Lin, Hui-Kuan
影响因子：
50.3
作者：
Elgendy, Mohamed;Ciro, Marco;Minucci, Saverio
通讯作者：
Minucci, Saverio