EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer
The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistical...
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Veröffentlicht in: | Cell reports (Cambridge) 2022-12, Vol.41 (11), p.111827-111827, Article 111827 |
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Zusammenfassung: | The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 leads to enhanced intratumoral CD8 T cell infiltration. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation and activation in lung cancer patient tumors. Our findings reveal a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offer an alternative combinatorial therapeutic strategy to target metastatic cancers with activated EGFRs that are often EGFR therapy resistant.
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•Dual targeting of RSK2 and GDH1 synergistically attenuates cancer metastasis•RSK2 and GDH1 coordinatively enhance the CREB activity•EGFR phosphorylates GDH1 at Y135 and activates GDH1•The activities of EGFR, GDH1, RSK2, and CREB correlate in primary patient tumors
Although oncogenic kinases are associated with human cancers, how they manage metabolic networks and cellular signaling to promote metastasis remains unclear. In this article, Kang et al. demonstrate a mechanism by which EGFR-activated GDH1 and RSK2 are intertwined to enhance CREB transcription activity and promote tumor metastasis in lung cancer. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2022.111827 |