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

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, 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 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.

Prognostic and clinicopathological role of RACK1 for cancer patients: a systematic review and meta-analysis

“…The included 22 studies were published between 2010 and 2022, with eleven studies (50%) published in the last five years ( Han et al, 2018 ; Li et al, 2019 ; Liu et al, 2017 ; Liu et al, 2018 ; Qu et al, 2017 ; Shen et al, 2020 ; Wu et al, 2020 ; Xiao et al, 2018 ; Xu et al, 2022 ; Yu et al, 2021 ; Zhang et al, 2019 ). One study was from Japan ( Nagashio et al, 2010 ) and the rest were from China ( Cao et al, 2010 ; Chen et al, 2015 ; Han et al, 2018 ; Jin et al, 2014 ; Li et al, 2016 ; Li et al, 2019 ; Lin et al, 2014 ; Liu et al, 2017 ; Liu et al, 2018 ; Lv et al, 2016 ; Peng et al, 2016 ; Qu et al, 2017 ; Shen et al, 2020 ; Shi et al, 2012 ; Wang et al, 2015 ; Wu et al, 2020 ; Xiao et al, 2018 ; Xu et al, 2022 ; Yu et al, 2021 ; Zhang et al, 2019 ; Zhong et al, 2013 ).…”

“…The included 22 studies were published between 2010 and 2022, with eleven studies (50%) published in the last five years ( Han et al, 2018 ; Li et al, 2019 ; Liu et al, 2017 ; Liu et al, 2018 ; Qu et al, 2017 ; Shen et al, 2020 ; Wu et al, 2020 ; Xiao et al, 2018 ; Xu et al, 2022 ; Yu et al, 2021 ; Zhang et al, 2019 ). One study was from Japan ( Nagashio et al, 2010 ) and the rest were from China ( Cao et al, 2010 ; Chen et al, 2015 ; Han et al, 2018 ; Jin et al, 2014 ; Li et al, 2016 ; Li et al, 2019 ; Lin et al, 2014 ; Liu et al, 2017 ; Liu et al, 2018 ; Lv et al, 2016 ; Peng et al, 2016 ; Qu et al, 2017 ; Shen et al, 2020 ; Shi et al, 2012 ; Wang et al, 2015 ; Wu et al, 2020 ; Xiao et al, 2018 ; Xu et al, 2022 ; Yu et al, 2021 ; Zhang et al, 2019 ; Zhong et al, 2013 ). The thirteen studies used to assess the prognostic value included fifteen independent cohorts, with three studies for PC ( Han et al, 2018 ; Li et al, 2016 ; Zhang et al, 2019 ), two studies each for GC ( Chen et al, 2015 ; Yu et al, 2021 ) and lung cancer (LC) ( Qu et al, 2017 ; Zhong et al, 2013 ), one study with three independent cohorts for OSCC ( Liu et al, 2018 ), and one study each for BC ( Cao et al, 2010 ), glioma ( Lv et al, 2016 ), ESCC ( Wang et al, 2015 ), cervical cancer (CC) ( Wu et al, 2020 ), and colorectal cancer (CRC) ( Xiao et al, 2018 ), totaling 2,620 patients.…”

“…The thirteen studies used to assess the prognostic value included fifteen independent cohorts, with three studies for PC ( Han et al, 2018 ; Li et al, 2016 ; Zhang et al, 2019 ), two studies each for GC ( Chen et al, 2015 ; Yu et al, 2021 ) and lung cancer (LC) ( Qu et al, 2017 ; Zhong et al, 2013 ), one study with three independent cohorts for OSCC ( Liu et al, 2018 ), and one study each for BC ( Cao et al, 2010 ), glioma ( Lv et al, 2016 ), ESCC ( Wang et al, 2015 ), cervical cancer (CC) ( Wu et al, 2020 ), and colorectal cancer (CRC) ( Xiao et al, 2018 ), totaling 2,620 patients. The 20 studies used to evaluate the association between clinicopathological features and RACK1 expression included four studies for LC ( Nagashio et al, 2010 ; Qu et al, 2017 ; Shi et al, 2012 ; Zhong et al, 2013 ), three studies each for GC ( Chen et al, 2015 ; Liu et al, 2017 ; Yu et al, 2021 ), PC ( Han et al, 2018 ; Li et al, 2016 ; Zhang et al, 2019 ), and CRC ( Jin et al, 2014 ; Li et al, 2019 ; Xiao et al, 2018 ), two studies for CC ( Wu et al, 2020 ; Xu et al, 2022 ), and one study each for BC ( Cao et al, 2010 ), ovarian cancer (OC)( Lin et al, 2014 ), ESCC ( Wang et al, 2015 ), melanoma ( Shen et al, 2020 ), and nasopharyngeal carcinoma (NPC) ( Peng et al, 2016 ), totaling 3,043 patients. The sample sizes of the cohorts included in the meta-analysis ranged from 50 to 495 patients, with a mean of 147 patients.…”

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/β-catenin signaling activation

“…Increased glycolysis has been coupled with various malignant phenotypes of CC cells, including tumor growth and metastasis [ 30 ]. Therefore, we investigated the impact of FAM83F on glycolysis in CC cells by measuring glucose uptake and ATP production after downregulation (Fig.…”

Tumor microenvironment promotes lymphatic metastasis of cervical cancer: its mechanisms and clinical implications

“…Upregulated expression of RACK1 promotes lymphangiogenesis via galectin-1 ( 44 ), which promotes lymphatic vascular growth and contributes to the maintenance of the lymphatic endothelial phenotype ( 45 ). In addition, RACK1 interacts with insulin−like growth factor 1 receptor (IGF1R) to promote lymphangiogenesis via activation of the AKT/mTOR pathway in CC cells ( 46 ). Hematological and neurological expressed 1 (HN1), a microtubule-associated protein, induces lymphangiogenesis by activating the NF-κB signaling pathway ( 47 ).…”