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As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.
RESUMO
Objective To evaluate the diagnostic value of the common test parameters in acute fever without obvious infection focus and sick appearance in children under 5 years.Methods The hospitalized children with fever duration less than 7 days, anal temperature higher than or equal to 38°C, age younger than or equal to 5 years, and without obvious infection focus and sick appearance were recruited, we investigated the diagnosis value of common test parameters including C-reactive protein (CRP), procalcitonin (PCT), the white blood cell count (WBC), and neutrophil percentage (N%) , according to the ifnal diagnostic.Results Of 228 children, 42 children (18.42%) had serious diseases, the difference of CRP, PCT between serious diseases group and non-serious diseases group were statistically signiifcant (P<0.001). The diagnostic cut-off point of CRP was 67.1 mg/L by speciifcity of 0.810 and sensitivity of 0.715, that of PCT was 0.505 ng/L by speciifcity 0.762 and sensitivity 0.672. The speciifcity and sensitivity combining CRP with PCT was respectively 0.918 and 0.617. Of 228 children, 32 children had viral infections, 40 children had bacterial infections, 15 children had mycoplasma infections. The difference of CRP, PCT, WBC, and N% among three groups were statistically signiifcant (P<0.01).The cut-off point of CRP was 38 mg/L by sensitivity 0.900 and spec-iifcity 0.813, that of PCT was 0.450 ng/L by sensitivity 0.700 and speciifcity 0.812, and the speciifcity and sensitivity combining CRP with PCT was respectively 0.965 and 0.630, to distinguish bacterial infections from viral infections. The diagnostic cut-off point of CRP was 80.75 mg/L by sensitivity 0.700 and speciifcity 0.933 distinguishing bacterial infections from mycoplasma infections.Conclusions The parameters CRP and PCT have the diagnostic value for the children with the acute fever and age younger than or equal to 5 years and without obvious infection focus and sick appearance in etiology and serious diseases, espe-cially the value of combining CRP with PCT is better.