6-磷酸葡萄糖脱氢酶通过抑制AMPK通路促进糖酵解和脂肪酸合成在肺腺癌细胞中的作用

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells

CANCER LETTERS

影响因子:10.1

分区:医学1区 Top / 肿瘤学2区

发表日期:2024 Oct 01

作者: Jun Wu, Yong Chen, Hui Zou, Kaiyue Xu, Jiaqi Hou, Mengmeng Wang, Shuyu Tian, Mingjun Gao, Qinglin Ren, Chao Sun, Shichun Lu, Qiang Wang, Yusheng Shu, Shouyu Wang, Xiaolin Wang

DOI: 10.1016/j.canlet.2024.217177

摘要

异常的代谢已成为癌症的一个显著特征，并在肺腺癌（LUAD）的发生和进展中起到关键作用。本研究中，单细胞测序显示，关键的代谢酶6-磷酸葡萄糖脱氢酶（PGD）作为五碳糖磷酸途径（PPP）的调控因子，在恶性进展过程中在恶性上皮细胞亚群中显著上调。然而，PGD在LUAD中的具体功能意义及其潜在机制仍不清楚。通过整合TCGA数据库分析和LUAD组织芯片数据，发现PGD在LUAD中显著上调，并与预后不良密切相关。此外，体外和体内分析表明，敲除PGD或抑制其活性可以减缓LUAD细胞的增殖、迁移和侵袭。机制上，免疫沉淀-质谱（IP-MS）首次发现IQGAP1是PGD的一个新颖的强效相互作用蛋白。PGD通过与已知的AMPKα结合伙伴IQGAP1的IQ结构域竞争性结合，降低p-AMPK水平，从而促进LUAD细胞中的糖酵解和脂肪酸合成。此外，我们还证实，Physcion（一种特异性抑制剂）与二甲双胍（AMPK激动剂）联合使用，能在体内外更有效地抑制肿瘤生长。这些发现表明PGD可能成为LUAD的潜在预后生物标志物和治疗靶点。

Abstract

Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.