6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1–AMPK signalling

Abstract

The oxidative pentose phosphate pathway (PPP) contributes to tumor growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumor growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signaling. Moreover, we identified and developed 6PGD inhibitors, Physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumor growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

RETRACTED ARTICLE: Physcion, a naturally occurring anthraquinone derivative, induces apoptosis and autophagy in human nasopharyngeal carcinoma

“…Recently, studies by Han's group have demonstrated that physcion not only acts as an apoptosis-inducing agent but also potentially suppress the metastasis of colorectal cancer [29,30,43] . Moreover, the modulatory effect of physcion on the metabolic function of tumor cells was also reported in a recent study, which showed that physcion suppressed cancer cell proliferation and tumor growth in nude mouse xenografts by inhibiting 6-phosphogluconate dehydrogenase [44] . In the present study, we provide the first evidence for the autophagy-inducing ability of physcion.…”

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Accordingly, the application of the PPARγ antagonist induced the phosphorylation of LKB1 (Figure 3e–h). LKB1 binds with pseudokinase Ste20‐related adaptor (STRAD) and scaffolding‐like adaptor protein mouse protein 25 (MO25) to form a complex, and it subsequently achieves full activation (Lin et al., 2015; Mihaylova & Shaw, 2011). We further demonstrated the impact of PPARγ antagonist on LKB1 activation using a co‐immunoprecipitation (Co‐IP) assay.…”

Oncogene-Directed Alterations in Cancer Cell Metabolism

“…Along this pathway, 6-phosphogluconate dehydrogenase, an enzyme that mediates the production of ribulose-5-phosphate, is also deregulated. Ribulose-5-phosphate inhibits AMPK activation by disrupting the active liver kinase B1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis [62]. …”