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

Xu,Lixiu; Li,Jinqiu; Tursun,Mikrban; Hai,Yan; Tursun,Hatila; Mamtimin,Batur; Hasim,Ayshamgul

doi:10.3892/ijo.2022.5373

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

Authors:
- Lixiu Xu
- Jinqiu Li
- Mikrban Tursun
- Yan Hai
- Hatila Tursun
- Batur Mamtimin
- Ayshamgul Hasim
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Affiliations: Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China, Department of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830017, P.R. China
Published online on: May 24, 2022 https://doi.org/10.3892/ijo.2022.5373
Article Number: 83
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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, 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 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 administration 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.

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