Ong Athena Jessica, Saeidi Soma, Chi Ngo Hoang Kieu, Kim Su Jung, Kim Do-Hee, Kim Seung Hyeon, Park Sin-Aye, Cha Young-Nam, Na Hye-Kyung, Surh Young-Joon
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
Free Radic Res. 2020 Dec;54(11-12):906-917. doi: 10.1080/10715762.2020.1761547. Epub 2020 May 27.
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 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 . 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 transcription.
最近的研究报告称，核因子红细胞2相关因子2（Nrf2）通过癌细胞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未完全清楚。戊糖磷酸途径（PPP）的一些酶被认为在癌症进展中起作用。本研究旨在探讨PPP酶之一的6-磷酸葡萄糖酸脱氢酶（PGD）在人肝癌HepG2细胞增殖和迁移中的潜在作用。Nrf2的基因敲除在转录和翻译水平上均减弱了PGD的表达。值得注意的是，Nrf2通过直接结合其启动子区域的抗氧化反应元件来调节PGD的转录。HepG2细胞中Nrf2的过表达导致增殖、存活和迁移增加，而这些事件通过沉默PGD而受到抑制。有趣的是，编码该酶的基因的敲低不仅减弱了HepG2细胞的增殖和克隆形成能力，还下调了Nrf2的表达。因此，Nrf2和PGD之间似乎存在一个正反馈环，肝癌细胞利用这个环来实现其增殖和存活。用PGD的催化产物5-磷酸核酮糖处理HepG2细胞，导致Nrf2浓度依赖性上调。总的来说，当前的研究表明，Nrf2部分通过诱导PGD转录促进肝癌细胞的生长和进展。
