Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells
Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells
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DOI：
10.1016/j.yexcr.2015.05.017
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发表时间：
2015-08-01
影响因子：
3.7
通讯作者：
Yeom, Young Ii
中科院分区：
文献类型：
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作者：
Kim, Dong Joon;Park, Young Soo;Yeom, Young Ii
尽管吉西他滨被广泛用作一线治疗药物，但由于化疗耐药机制尚不清楚，它在晚期胰腺癌中的疗效有限。我们的目标是确定与吉西他滨化疗耐药有关的分子特征。丙酮酸激酶M2(PKM2)是有氧糖酵解的关键酶，近年来已成为肿瘤治疗的重要靶点。它参与了癌细胞的代谢重新编程，并具有先前意想不到的非代谢功能，这些功能与肿瘤的生长和生存密切相关。在此，我们报道胰腺癌对吉西他滨的化疗耐药依赖于PKM2的表达及其非代谢功能。敲除PKM2可通过激活caspase3/7和PARP裂解显著增强吉西他滨诱导的细胞凋亡，这种抑制作用与p38介导的丝氨酸46处的P53磷酸化有关。我们的发现支持PKM2作为吉西他滨化疗耐药的新靶点的潜力，并提示联合吉西他滨和PKM2抑制用于改善胰腺癌化疗的可行性。(C)2015 Elsevier Inc.保留所有权利。
Despite its wide use as a first-line therapeutic agent, gemcitabine has shown limited efficacy in advanced pancreatic cancer due to chemoresistance by as yet unidentified mechanisms. Our goal here was to identify molecular features involved in gemcitabine chemoresistance. Pyruvate kinase M2 (PKM2), a key enzyme of aerobic glycolysis, has recently emerged as an important therapeutic target for cancer treatment. It is involved in the metabolic reprogramming of cancer cells and has previously unexpected non-metabolic functions that are heavily involved in tumor growth and survival. Herein, we report that the chemoresistance of pancreatic cancer to gemcitabine was dependent on PKM2 expression and its non-metabolic function. Knocking-down of PKM2 significantly enhanced gemcitabine-induced cell apoptosis through the activation of caspase 3/7 and PARP cleavage, and this inhibitory activity was associated with p38-mediated activation of p53 phosphorylation at serine 46. Our findings support the potential of PKM2 as a novel target for gemcitabine chemoresistance and suggest the feasibility of combining gemcitabine and PKM2 inhibition for the improved chemotherapy of pancreatic cancer. (C) 2015 Elsevier Inc. All rights reserved.