Abstract 961: 6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling

Abstract

Abstract 6-phosphogluconate dehydrogenase (6PGD) in the oxidative pentose phosphate pathway (PPP) is upregulated in many cancers. However, how 6PGD is activated and provides a metabolic advantage to tumor growth is unknown. Here we show that 6PGD is commonly activated in human cancers by acetylation at K76 and K294,We found that 6PGD is commonly activated in human cancers by lysine acetylation. Acetylation at K76 and K294 promotes NADP+-binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we found that lysine acetylation of 6PGD is important for cancer cell metabolism, proliferation and tumor growth. We also performed systematic RNAi screens and identified DLAT and ACAT2 as 6PGD acetyltransferases and HDAC4 as 6PGD deacetylase, using two novel “targeted” shRNA libraries that target the majority of acetyltransferases and deacetylases in the human genome, respectively. In addition, we found that 6PGD controls intracellular levels of its product ribulose-5-phosphate (Ru-5-P) to regulate lipogenesis. Ru-5-P inhibits LKB1 by disrupting active LKB1 complex, leading to inhibition of AMPK and subsequent activation of acetyl-CoA carboxylase 1 and lipogenesis. Furthermore, we screened out Physcion and its derivative S3 as novel 6PGD inhibitors, which are efficacious in treatment of xenograft nude mice and primary leukemia cells from human patients with minimal toxicity and no off-target effect. Our findings for the first time decipher the molecular mechanisms underlying 6PGD upregulation in cancer cells and suggest that 6PGD provides an additional and novel link between oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signaling. Moreover, identification and characterization of 6PGD inhibitors in translational/pre-clinical studies for the first time provide “proof of principle” to suggest 6PGD as an attractive anti-cancer target. Citation Format: Changliang Shan, Shannon E. Elf, Ting-Lei Gu, Hanna J. Khoury, Titus Boggon, Sumin Kang, Jing Chen. 6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 961. doi:10.1158/1538-7445.AM2014-961