Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.
Pancreatic Cancer Institute, Fudan University, Shanghai, P.R. China.
Int J Oncol. 2017 May;50(5):1792-1800. doi: 10.3892/ijo.2017.3938. Epub 2017 Mar 28.
N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1α level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1α, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC.
N-myc 下游调节基因 1（NDRG1）在包括胰腺在内的多种癌症中被称为肿瘤/转移抑制因子，参与血管生成、癌症生长和转移。然而，NDRG1 在胰腺癌中发挥抑制功能的确切分子机制尚不清楚。在这项研究中，我们证明了 K-Ras 在体外调节 PDAC 癌细胞中 NDRG1 蛋白水平方面起着至关重要的作用，这是通过 ERK 信号传导介导的。值得注意的是，NDRG1 的过表达抑制了 K-Ras 下游 Akt/mTOR 信号传导，导致 HIF1α 水平下降。此外，NDRG1 在调节胰腺导管腺癌（PDAC）的癌症代谢方面具有独特的作用。NDRG1 调节有氧糖酵解的机制至少部分依赖于其对糖酵解基因的调节，包括 GLUT1、HK2、LDHA 和 PDK1。此外，NDRG1 被证明可以抑制 HIF1α 的活性，HIF1α 负责调节糖酵解酶。本研究首次阐明了强效肿瘤/转移抑制因子 NDRG1 在调节 PDAC 糖酵解方面的独特作用，为深入了解 NDRG1 在 PDAC 中发挥抑制功能的机制提供了重要线索。
