Receptor for activated C kinase 1 promotes cervical cancer lymph node metastasis via the glycolysis-dependent AKT/mTOR signaling

Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early-stage lymph node metastasis and an extremely poor prognosis. The authors have previously demonstrated that patients with CC have aberrant glycolysis. The upregulation of receptor for activated C kinase 1 (RACK1) is associated with CC lymph node metastasis (LNM). However, its role in mediating aerobic glycolysis in CC LNM remains unclear. In the present study, (1)H nuclear magnetic resonance analysis revealed a significant association between RACK1 expression and the glycolysis/gluconeogenesis pathway. Additionally, RACK1 knockdown inhibited aerobic glycolysis and lymphangiogenesis in vitro and suppressed CC LNM in vivo. Furthermore, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was identified as a critical RACK1-regulated pathway that increased lymphangiogenesis in CC. Co-immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin-like growth factor 1 receptor (IGF1R). POU class 2 homeobox 2 (POU2F2) bound to the RACK1 promoter and regulated its transcription, thereby functionally contributing to glycolysis and lymphangiogenesis in CC. Of note, the admin-istration of 2-deoxy-D-glucose, which attenuates glycolysis, inhibited RACK1-induced lymphangiogenesis in CC. The correlations between RACK1, IGF1R, POU2F2 and hexokinase 2 were further confirmed in CC tissues. Thus, RACK1 plays a crucial role in CC tumor LNM by regulating glycolysis via IGF1R/AKT/mTOR signaling. Thus, the targeting of the POU2F2/RACK1/IGF1R/AKT/mTOR signaling pathway may provide a novel treatment strategy for CC.