Abstract

Recent studies report that nuclear factor-erythroid-2-related factor 2 (Nrf2) facilitates tumor progression through metabolic reprogramming in cancer cells. However, the molecular mechanism underlying the oncogenic functions of Nrf2 is not yet well understood. Some of the pentose phosphate pathway (PPP) enzymes are considered to play a role in the cancer progression. The present study was intended to explore the potential role of phosphogluconate dehydrogenase (PGD), one of the PPP enzymes, in the proliferation and migration of human hepatoma HepG2 cells. Genetic ablation of Nrf2 attenuated the expression of PGD at both transcriptional and translational levels. Notably, Nrf2 regulates the transcription of PGD through direct binding to the antioxidant response element in its promoter region. Nrf2 overexpression in HepG2 cells led to increased proliferation, survival, and migration, and these events were suppressed by silencing PGD. Interestingly, knockdown of the gene encoding this enzyme not only attenuated the proliferation and clonogenicity of HepG2 cells but also downregulated the expression of Nrf2. Thus, there seems to exist a positive feedback loop between Nrf2 and PGD which is exploited by hepatoma cells for their proliferation and survival. Treatment of HepG2 cells with ribulose-5-phosphate, a catalytic product of PGD, gave rise to a concentration-dependent upregulation of Nrf2. Collectively, the current study shows that Nrf2 promotes hepatoma cell growth and progression, partly through induction of PGD transcription.

摘要

最近的研究报告称，核因子-erythroid-2 相关因子 2 (Nrf2) 通过癌细胞中的代谢重编程促进肿瘤进展。然而，Nrf2 致癌功能的分子机制尚不清楚。一些戊糖磷酸途径 (PPP) 酶被认为在癌症进展中起作用。本研究旨在探讨磷酸葡萄糖酸脱氢酶 (PGD)（一种 PPP 酶）在人肝癌 HepG2 细胞增殖和迁移中的潜在作用。Nrf2 的遗传消融减弱了 PGD 在转录和翻译水平上的表达。值得注意的是，Nrf2 调节PGD的转录通过直接结合其启动子区域的抗氧化反应元件。HepG2 细胞中的 Nrf2 过表达导致增殖、存活和迁移增加，并且这些事件通过沉默PGD被抑制。有趣的是，敲低编码该酶的基因不仅减弱了 HepG2 细胞的增殖和克隆形成，而且还下调了 Nrf2 的表达。因此，Nrf2 和 PGD 之间似乎存在正反馈回路，肝癌细胞利用该回路进行增殖和存活。用 5-磷酸核酮糖（PGD 的一种催化产物）处理 HepG2 细胞会导致 Nrf2 的浓度依赖性上调。总的来说，目前的研究表明 Nrf2 促进肝癌细胞的生长和进展，部分是通过诱导PGD转录。