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Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2021-09-11 , DOI: 10.1016/j.apsb.2021.09.007
Cancan Zheng 1 , Xiaomei Yu 1 , Yiyao Liang 2 , Yidong Zhu 3 , Yan He 3 , Long Liao 1 , Dingkang Wang 1 , Yanming Yang 1 , Xingfeng Yin 1 , Ang Li 2 , Qingyu He 1 , Bin Li 1
Affiliation  

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.



中文翻译:

五氟利多靶向PFKL抑制糖酵解并以AMPK/FOXO3a/BIM依赖性方式抑制食管癌肿瘤发生

作为癌症的标志之一,代谢重编程导致癌症进展,靶向糖酵解酶可能是癌症治疗的有用策略。通过筛选由 1320 种 FDA 批准的药物组成的小分子库,我们发现用于治疗精神分裂症的抗精神病药物五氟利多可以抑制食管鳞状细胞癌 (ESCC) 的糖酵解并诱导细胞凋亡。基因分析和Ingenuity Pathway分析提示AMPK在五氟利多作用机制中的重要作用。通过使用药物亲和力响应靶稳定性 (DARTS) 技术和蛋白质组学,我们确定了磷酸果糖激酶,肝型 (PFKL),一种糖酵解中的关键酶,作为五氟利多的直接靶标。Penfluridol 不能在 PFKL 缺陷的癌细胞中表现出其抗癌特性,说明PFKL对于五氟利多的生物活性是必不可少的。PFKL 的高表达与 ESCC 患者的晚期和较差的生存率相关,PFKL 的沉默显着抑制了肿瘤的生长。机制上,五氟利多和 PFKL 的直接结合抑制葡萄糖消耗、乳酸和 ATP 产生,导致 FOXO3a 的核易位和随后的转录激活以 AMPK 为依赖方式的BIM。总而言之,PFKL 是 ESCC 的潜在预后生物标志物和治疗靶点,五氟利多可能是治疗这种致命疾病的新治疗选择。

更新日期:2021-09-11
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