Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation
Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation
复制标题
丙酮酸脱氢酶激酶 1 通过 EGFR 激活导致卵巢癌顺铂耐药
DOI：
10.1002/jcp.27369
复制
发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Xu, Cong-Jian
中科院分区：
文献类型：
--
作者：
Zhang, Meng;Cong, Qing;Xu, Cong-Jian
卵巢癌患者在长期化疗后经常出现获得性耐药，导致疾病进展。增强的上皮-间质转化（EMT）与卵巢癌细胞的化疗耐药性有关;然而，所涉及的分子机制在很大程度上尚未确定。丙酮酸脱氢酶激酶1（PDK 1）是葡萄糖代谢的关键调节酶，被认为是肿瘤标志性瓦尔堡效应的守门人。本研究从生长和EMT两个方面探讨PDK 1在卵巢癌顺铂耐药中的作用。PDK 1在顺铂耐药的卵巢癌细胞中上调。PDK 1在耐药细胞中的敲低导致对顺铂诱导的细胞死亡和凋亡的敏感性增加。PDK 1下调也逆转了顺铂耐药细胞的EMT和细胞运动性。在小鼠异种移植模型中，与顺铂治疗后的对照相比，来自PDK 1沉默的卵巢癌细胞的肿瘤表现出肿瘤生长和EMT降低。从机制上讲，PDK 1过表达导致EGFR磷酸化增加，厄洛替尼阻断EGFR激酶活性可逆转PDK 1过表达诱导的顺铂耐药。此外，在卵巢癌患者中，较高的PDK 1和p-EGFR水平与化疗耐药性相关。这些结果支持PDK 1通过激活EGFR参与卵巢癌的化疗耐药。因此，PDK 1可能成为对抗卵巢癌化疗耐药的一个有希望的靶点。
Patients with ovarian cancer frequently develop acquired drug resistance after the long-term chemotherapy, leading to disease progression. Enhanced epithelial-mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated. PDK1 was upregulated in cisplatin-resistant ovarian cancer cells. PDK1 knockdown in resistant cells led to increased sensitivity to cisplatin-induced cell death and apoptosis. PDK1 downregulation also reversed the EMT and cell motility in cisplatin-resistant cells. In a mouse xenograft model, tumors derived from PDK1-silenced ovarian cancer cells exhibited decreased tumor growth and EMT compared with control after the cisplatin treatment. Mechanistically, PDK1 overexpression led to increased phosphorylation of EGFR, and blocking EGFR kinase activity by erlotinib reversed cisplatin resistance induced by PDK1 overexpression. Furthermore, in patients with ovarian cancer, higher PDK1 and p-EGFR levels were associated with chemoresistance. These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR. Therefore, PDK1 may serve as a promising target to combat chemoresistance of ovarian cancer.