ABSTRACT
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.
ABSTRACT
Objective To identify and analyze plasma membrane proteins differentially expressed between fluconazole-sensitive and-resistant C.albicans strains.Methods Two C.albicans strains from a same parent,including the fluconazole-sensitive C.albicans strain CA-3 and fluconazole-resistant C.albicans strain CA-16,served as the subject of this study.Plasma membrane proteins were isolated from both of the C.albicans strains,and subjected to two-dimensional polyacrylamide gel electrophoresis analysis for the screening of differentially expressed proteins,which were then identified by using matrix assisted laser desorption/ionization time-of-flight mass spectrometry.The resultant data were searched against a protein database for C.albicans.Results Twentytwo proteins were identified to be differentially expressed between the fiuconazole-resistant and-sensitive C.albicans strain.Of them,6 proteins (Adh1p,Csp37p,Pgk1p,Pgk1p and 2 unnamed proteins,i.e.,gi227305312and gi53954641) were highly expressed,while 16 proteins (Aco1p,Aco1p,Hsp78p,Gut2p,Sdh12p,Ilv2p,Ndh51p,Ndh51p,Atp1p,Pda1p,Srb1p,Idh1p,Tdh1p,Cyt1p,Cox4p,Cox13p) were lowly expressed in the fluconazole-resistant C.albicans strain compared with the fluconazole-sensitive strain.Conclusion The plasma membrane proteins differentially expressed between fluconazole-sensitive and-resistant C.albicans strain are mainly implicated in energy metabolism and mitochondrial function.