Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710000, Shaanxi, China.
Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710000, Shaanxi, China.
Cancer Chemother Pharmacol. 2021 Feb;87(2):207-215. doi: 10.1007/s00280-020-04188-9. Epub 2020 Nov 21.
The use of cisplatin for the treatment of non-small cell lung cancer has long been constrained by the rapid acquisition of tumor cell chemoresistance. In the present study, we sought to better elucidate the molecular mechanisms underlying this resistance phenotype. To that end, we assessed gene expression patterns in cisplatin-resistant lung adenocarcinoma cells, revealing pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) to be the most up-regulated kinase in resistant cells. We further found PDK4 upregulation to be directly linked with the acquisition of chemoresistance, driving enhanced tumor cell growth in vitro and in vivo. In clinical samples, we also found that PDK4 upregulation was detectable in patients with lung adenocarcinoma and that it was correlated with a poorer prognosis for these patients. From a mechanistic perspective, we further determined that PDK4 was able to promote lung adenocarcinoma cell growth and cisplatin resistance at least in part via regulating endothelial PAS domain-containing protein 1 (EPAS1) expression, thus highlighting PDK4 as a potentially viable therapeutic target in efforts to treat lung adenocarcinoma patients that have become resistant to cisplatin.
顺铂治疗非小细胞肺癌的应用长期以来受到肿瘤细胞快速获得化疗耐药性的限制。在本研究中，我们试图更好地阐明这种耐药表型的分子机制。为此，我们评估了顺铂耐药肺腺癌细胞中的基因表达模式，结果表明，丙酮酸脱氢酶激酶同工酶 4（PDK4）是耐药细胞中上调最明显的激酶。我们进一步发现 PDK4 的上调与获得化疗耐药性直接相关，促进了体外和体内肿瘤细胞的生长。在临床样本中，我们还发现 PDK4 的上调可在肺腺癌患者中检测到，并且与这些患者的预后较差相关。从机制角度来看，我们进一步确定 PDK4 至少部分通过调节内皮 PAS 结构域蛋白 1（EPAS1）的表达来促进肺腺癌细胞的生长和对顺铂的耐药性，从而凸显了 PDK4 作为治疗对顺铂耐药的肺腺癌患者的潜在可行的治疗靶点。
