Abstract
BackgroundThe study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer.MethodsThe maximum standard uptake value (SUVmax) of tumors was detected by18F-FDG PET/CT scan. In vitro, glycolysis analysis, extracellular acidification rate analysis, and ATP production were used to evaluate the impact of PIK3CA E542K and E545K mutations on glucose metabolism. The expression level of key glycolytic enzymes was evaluated by western blotting and immunohistochemical staining in cervical cancer cells and tumor tissues, respectively. Immunofluorescence analysis was used to observe the nuclear translocation of β-catenin. The target gene of β-catenin was analyzed by using luciferase reporter system. The glucose metabolic ability of the xenograft models was assessed by SUVmax from microPET/CT scanning.ResultsCervical cancer patients with mutant PIK3CA (E542K and E545K) exhibited a higher SUVmax value than those with wild-type PIK3CA (P = 0.037), which was confirmed in xenograft models. In vitro, enhanced glucose metabolism and proliferation was observed in SiHa and MS751 cells with mutant PIK3CA. The mRNA and protein expression of key glycolytic enzymes was increased. AKT/GSK3β/β-catenin signaling was highly activated in SiHa and MS751 cells with mutant PIK3CA. Knocking down β-catenin expression decreased glucose uptake and lactate production. In addition, the nuclear accumulation of β-catenin was found in SiHa cells and tumors with mutant PIK3CA. Furthermore, β-catenin downregulated the expression of SIRT3 via suppressing the activity of the SIRT3 promotor, and the reduced glucose uptake and lactate production due to the downregulation of β-catenin can be reversed by the transfection of SIRT3 siRNA in SiHa cells with mutant PIK3CA. The negative correlation between β-catenin and SIRT3 was further confirmed in cervical cancer tissues.ConclusionsThese findings provide evidence that the PI3K E542K and E545K/β-catenin/SIRT3 signaling axis regulates glucose metabolism and proliferation in cervical cancers with PIK3CA mutations, suggesting therapeutic targets in the treatment of cervical cancers.Trial registrationFUSCC 050432–4-1212B. Registered 24 December 2012 (retrospectively registered).
Highlights
The study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer
Mutant phosphatidylinositol 3-kinase (PI3K) enhanced the expression of β-catenin by activating AKT/GSK3β signaling and promoted the nuclear translocation of β-catenin to transcriptionally decrease the expression of SIRT3, which is a negative regulator of glucose metabolism. These results indicate that PIK3CA E542K and E545K mutations play a positive role in regulating glucose metabolism by activating β-catenin/SIRT3 signaling pathways in cervical cancer
PIK3CA E542K and E545K mutations promote glucose metabolism and proliferation in cervical cancer cells To further determine the function of PI3K E542K and E545K in cervical cancer, we introduced PI3K E542K and E545K cDNA into SiHa and MS751 cells and established SiHa/PI3K E542K, SiHa/PI3K E545K, MS751/PI3K E542K, and MS751/PI3K E545K cells stably expressing PI3K E542K and E545K cDNA (Fig. 2a)
Summary
The study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer. Increasing studies have focused on exploring the molecular characteristics of cervical cancer to identify new therapeutic targets to improve the prognosis of this disease. Molecular aberrations of the PI3K pathway drive tumorigenesis and promote various biological processes, including cell proliferation, invasion and migration, differentiation, apoptosis, and glucose metabolism [2,3,4]. These alterations are mainly caused by PIK3CA amplification or mutation [5, 6] and PTEN loss [7]. PIK3CA mutations in helical and kinase domains exhibit distinct biological and clinical characteristics due to the activation of different signaling pathways. It is necessary to elucidate the regulatory function of the mutated hotspots E542K and E545K in cervical cancer
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