Receptor for activated C kinase 1 promotes cervical cancer lymph node metastasis via the glycolysis­dependent AKT/mTOR signaling.

Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early­stage 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, 1H 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 RACK1­regulated pathway that increased lymphangiogenesis in CC. Co­immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin­like 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 administration of 2­deoxy­D­glucose, which attenuates glycolysis, inhibited RACK1­induced 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.