Department of Urology, New York University Langone Health, New York, New York.
Veterans Affairs New York Harbor Healthcare System, New York, New York.
Cancer Res. 2022 Feb 15;82(4):571-585. doi: 10.1158/0008-5472.CAN-21-0403.
Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade nonmuscle-invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1α/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.
Genetic manipulation and pharmacologic inhibition of PKM2 in mouse urothelial lesions highlight its essential role in promoting angiogenesis and metabolic addiction, events indispensable for tumor growth and maintenance.
丙酮酸激酶 M2（PKM2）已被证明通过促进瓦博格效应和增强癌蛋白活性来促进肿瘤发生。然而，最近的研究挑战了这一范式，在这些研究中，缺乏 PKM2 不仅未能抑制肿瘤发生，反而加速了小鼠模型中的肿瘤发生。这些结果似乎与大多数人类肿瘤过度表达 PKM2 的事实不一致。为了进一步阐明 PKM2 在肿瘤发生中的作用，我们研究了 PKM2 缺失对致癌性 HRAS 驱动的尿路上皮癌的影响。虽然 PKM2 缺失在小鼠尿路上皮细胞中不影响肿瘤起始，但它会损害 HRAS 驱动的肿瘤的生长和维持。PKM2 的化学抑制作用再现了这些效果。这两种情况都大大减少了 PKM2 与 STAT3 的复合物形成、它们的核转位以及 HIF1α 和 VEGF 相关的血管生成。PKM2 缺失时核 STAT3 的减少也与自噬减少和细胞凋亡增加相关。在简单的尿路上皮增生中进行时间控制、诱导性 PKM2 过表达不会引发肿瘤发生，而在有血管生成的结节性尿路上皮增生中 PKM2 而不是 PKM1 的过表达则强烈加速了肿瘤发生。最后，在人类患者中，低级别非肌肉浸润性和高级别肌肉浸润性膀胱癌中 PKM2 过表达。基于这些数据，PKM2 不是肿瘤起始所必需的，但通过增强血管生成和代谢成瘾对肿瘤生长和维持是必不可少的。PKM2-STAT3-HIF1α/VEGF 信号轴可能在膀胱癌中起关键作用，并可能成为可操作的治疗靶点。
在小鼠尿路上皮病变中对 PKM2 的遗传操作和药物抑制强调了其在促进血管生成和代谢成瘾中的关键作用，这些事件对于肿瘤生长和维持是不可或缺的。
