Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Am J Pathol. 2011 Sep;179(3):1405-14. doi: 10.1016/j.ajpath.2011.05.050. Epub 2011 Jul 18.
The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis (n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy.
细胞代谢从线粒体呼吸向糖酵解的转变是癌细胞的标志，与肿瘤恶性程度相关。丙酮酸脱氢酶激酶-1（PDK1）和 PDK3 参与癌细胞的代谢转换；然而，PDK1 和 PDK3 在癌症进展中的医学意义尚不清楚。在这里，我们评估了 PDK1 和 PDK3 在结直肠癌中的表达谱。Western blot 分析（n = 74）表明，与相邻正常组织相比，PDK3 在结肠癌中明显增加，而 PDK1 在癌细胞中减少。此外，PDK3 的表达与癌细胞中缺氧诱导因子-1α（HIF-1α）的表达呈正相关。使用免疫组织化学染色的进一步分析表明，PDK3 水平与癌症的严重程度呈正相关，与无病生存率呈负相关。使用几种结肠癌细胞系进行的体外研究表明，PDK3 的表达受 HIF-1α 控制，并有助于缺氧诱导的耐药性增加，这也许可以解释为什么 PDK3 过表达的患者更易发生治疗失败。综上所述，我们的研究结果表明，PDK3 在结肠癌的代谢转换和耐药性中发挥重要作用，可能是癌症治疗的一个新靶点。
