Zhang Yang, Zhang Yi, Geng Liying, Yi Haowei, Huo Wei, Talmon Geoffrey, Kim Yeong C, Wang San Ming, Wang Jing
From the Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, and Departments of Genetics, Cell Biology, and Anatomy.
the Department of Cell Biology, Third Military Medical University, Chongqing 400038, China, and.
J Biol Chem. 2016 Aug 12;291(33):17405-16. doi: 10.1074/jbc.M116.713735. Epub 2016 Jun 21.
Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.
耐药性是结肠癌复发的主要原因之一。然而，我们对其潜在机制的理解以及治疗选择仍然有限。在此我们表明，丙酮酸脱氢酶激酶4（PDK4）的表达与结肠癌细胞的耐药性呈正相关，并且在耐药而非敏感细胞中由5-氟尿嘧啶（5-FU）处理诱导产生。敲低PDK4表达可使结肠癌细胞在体外对5-FU或奥沙利铂诱导的凋亡敏感，并在体内小鼠异种移植模型中增强5-FU抑制肿瘤生长的有效性。此外，我们首次证明TGFβ通过调节PDK4表达介导耐药性，并且5-FU以TGFβ信号依赖的方式诱导PDK4表达。从机制上讲，敲低或抑制PDK4可显著增强5-FU对抗凋亡因子Bcl-2和survivin表达的抑制作用。重要的是，对患者样本的研究表明，PDK4的表达与TGFβ通路激活指标Smad2的磷酸化呈强相关，并且两者均与结直肠癌的化疗耐药正相关。这些发现表明，TGFβ/PDK4信号轴在结直肠癌对化疗的反应中起重要作用。我们研究的一个主要意义在于，抑制PDK4可能具有克服结直肠癌患者耐药性的巨大治疗潜力，这值得开发PDK4特异性抑制剂。
