Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes.
Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes.
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DOI：
10.1158/0008-5472.can-20-4190
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发表时间：
2021-08-15
期刊：
影响因子：
11.2
通讯作者：
Rinehart J
中科院分区：
文献类型：
--
作者：
Apostolidi M;Vathiotis IA;Muthusamy V;Gaule P;Gassaway BM;Rimm DL;Rinehart J
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，生存率低，缺乏生物标志物和靶向治疗。在这里，我们靶向丙酮酸激酶M2（PKM 2），肿瘤发生的关键代谢成分。在TNBC患者中，PKM 2 pS37被鉴定为对应于侵袭性乳腺癌表型的显著磷蛋白，其显示特征性核染色模式和预后价值。在TNBC细胞中，PKM 2在S37处的磷酸化与细胞周期蛋白依赖性激酶（CDK）通路相关。同时，丙酮酸激酶激活剂TEPP-46结合PKM 2 pS37并减少其核定位。在TNBC小鼠异种移植模型中，用TEPP-46或强效CDK抑制剂Dinaciclib治疗可减少肿瘤生长并减少PKM 2 pS37。Dinaciclib与TEPP-46的组合减少了细胞侵袭，损害了氧化还原平衡，并引发了癌细胞死亡。总的来说，这些数据支持鉴定PKM 2 pS37阳性TNBC并靶向PKM 2调节轴作为潜在治疗的方法。
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low survival rate and a lack of biomarkers and targeted treatments. Here we target pyruvate kinase M2 (PKM2), a key metabolic component of oncogenesis. In TNBC patients, PKM2pS37 was identified as a prominent phosphoprotein corresponding to the aggressive breast cancer phenotype that showed a characteristic nuclear staining pattern and prognostic value. Phosphorylation of PKM2 at S37 was connected with a cyclin-dependent kinase (CDK) pathway in TNBC cells. In parallel, pyruvate kinase activator TEPP-46 bound PKM2pS37 and reduced its nuclear localization. In a TNBC mouse xenograft model, treatment with either TEPP-46 or the potent CDK inhibitor Dinaciclib reduced tumor growth and diminished PKM2pS37. Combinations of Dinaciclib with TEPP-46 reduced cell invasion, impaired redox balance, and triggered cancer cell death. Collectively, these data support an approach to identify PKM2pS37-positive TNBC and target the PKM2 regulatory axis as a potential treatment.