Advanced bladder cancer remains a major source of mortality, with poor treatment options. Cisplatin-based chemotherapy is the standard treatment, however many patients are or become resistant. One potential cause of chemoresistance is the Warburg effect, a metabolic switch to aerobic glycolysis that occurs in many cancers. Upregulation of the pyruvate dehydrogenase kinase family (PDK1–PDK4) is associated with aerobic glycolysis and chemoresistance through inhibition of the pyruvate dehydrogenase complex (PDH). We have previously observed upregulation of PDK4 in high-grade compared with low-grade bladder cancers. We initiated this study to determine if inhibition of PDK4 could reduce tumor growth rates or sensitize bladder cancer cells to cisplatin. Upregulation of PDK4 in malignant bladder cancer cell lines as compared with benign transformed urothelial cells was confirmed using qPCR. Inhibition of PDK4 with dichloroacetate (DCA) resulted in increased PDH activity, reduced cell growth, and G0–G1 phase arrest in bladder cancer cells. Similarly, siRNA knockdown of PDK4 inhibited bladder cancer cell proliferation. Cotreatment of bladder cancer cells with cisplatin and DCA did not increase caspase-3 activity but did enhance overall cell death in vitro. Although daily treatment with 200 mg/kg DCA alone did not reduce tumor volumes in a xenograft model, combination treatment with cisplatin resulted in dramatically reduced tumor volumes as compared with either DCA or cisplatin alone. This was attributed to substantial intratumoral necrosis. These findings indicate inhibition of PDK4 may potentiate cisplatin-induced cell death and warrant further studies investigating the mechanism through which this occurs. Mol Cancer Ther; 17(9); 2004–12. ©2018 AACR.

中文翻译：

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丙酮酸脱氢酶激酶 4 (PDK4) 在膀胱癌和化疗耐药中的作用

晚期膀胱癌仍然是死亡的主要来源，治疗选择不佳。以顺铂为基础的化疗是标准治疗方法，但许多患者已经或变得耐药。化学抗性的一个潜在原因是 Warburg 效应，这是一种在许多癌症中发生的向有氧糖酵解的代谢转变。丙酮酸脱氢酶激酶家族 (PDK1-PDK4) 的上调通过抑制丙酮酸脱氢酶复合物 (PDH) 与有氧糖酵解和化学抗性相关。我们之前已经观察到与低级别膀胱癌相比，高级别膀胱癌中 PDK4 的上调。我们发起了这项研究，以确定抑制 PDK4 是否可以降低肿瘤生长速度或使膀胱癌细胞对顺铂敏感。使用 qPCR 证实了与良性转化的尿路上皮细胞相比，恶性膀胱癌细胞系中 PDK4 的上调。用二氯乙酸 (DCA) 抑制 PDK4 导致膀胱癌细胞中 PDH 活性增加、细胞生长减少和 G0-G1 期停滞。类似地，PDK4 的siRNA 敲低抑制膀胱癌细胞增殖。用顺铂和 DCA 共同处理膀胱癌细胞并没有增加 caspase-3 的活性，但在体外确实增强了整体细胞死亡。尽管每天单独使用 200 mg/kg DCA 治疗不会减少异种移植模型中的肿瘤体积，但与单独使用 DCA 或顺铂相比，与顺铂联合治疗导致肿瘤体积显着减少。这归因于大量的瘤内坏死。这些发现表明 PDK4 的抑制可能会加强顺铂诱导的细胞死亡，并需要进一步研究调查发生这种情况的机制。摩尔癌症治疗; 17(9); 2004-12。©2018 AACR。