Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis

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. 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 3 beta (GSK3 beta), 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, GSK3 beta-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3 beta, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3 beta-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 GSK3 beta-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy.

Automated summary

The combination of intermittent fasting and chemotherapy can improve treatment efficacy, with the GSK3β-SIRT7 axis playing a crucial role. This mechanism is likely regulated by AMPK and GSK3β.