PKM2 的下调增强了 THP 对膀胱癌的抗癌效率。
Down-regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer.
机构信息
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education of China), Hunan Normal University, Changsha, Hunan, China.
出版信息
J Cell Mol Med. 2018 May;22(5):2774-2790. doi: 10.1111/jcmm.13571. Epub 2018 Mar 7.
Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non-muscle-invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down-regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches. Molecular mechanisms of PKM2 on THP sensitization were explored by probing p-AMPK and p-STAT3 levels via WB. Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan-Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM2 was overexpressed in bladder cancer cells and tissues, and down-regulation of PKM2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti-bladder cancer activities. On the other hand, down-regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity. Compared with THP alone (400 μmol L , 50 μL), the combination with metformin (60 mmol L , 50 μL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down-regulating the expression of PKM2 enhances the anticancer efficiency of THP. This study provides a new insight for improving the chemotherapeutic effect of THP.
丙酮酸激酶 M2（PKM2）调节糖酵解水平的最后一步，与抗癌化疗药物的敏感性相关。THP 是用于非肌肉浸润性膀胱癌灌注化疗的主要药物之一。然而，在使用胶原凝胶基质的人类泌尿生殖系统肿瘤中，观察到 THP（19.7%）治疗的低反应率。本研究旨在探讨下调 PKM2 对 THP 效率的影响。通过抑制剂或 siRNA，在 2 个人类和 1 个鼠类膀胱癌细胞系中，使用 MTT、cologenic 和荧光方法，确定减少 PKM2 对 THP 效率的影响。通过 WB 探测 p-AMPK 和 p-STAT3 水平，探讨 PKM2 对 THP 增敏的分子机制。应用同基因原位膀胱癌模型在体内评估这种效率，通过 Kaplan-Meier 生存曲线、体重和膀胱重量以及免疫组织化学肿瘤生物标志物进行分析。PKM2 在膀胱癌细胞和组织中过度表达，下调 PKM2 增强了 THP 的体外敏感性。AMPK 的激活对于 THP 发挥抗膀胱癌活性是必不可少的。另一方面，下调 PKM2 激活 AMPK 并抑制 STAT3，与 THP 敏感性相关。与单独使用 THP（400 μmol L，50 μL）相比，与二甲双胍（60 mmol L，50 μL）联合使用完全阻止了体内膀胱癌的生长（联合组与正常组 P =.078）。下调 PKM2 的表达增强了 THP 的抗癌效率。本研究为提高 THP 的化疗效果提供了新的见解。
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