Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase.
Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase.
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DOI：
10.1186/s40170-020-00226-5
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发表时间：
2020
影响因子：
5.9
通讯作者：
Bhardwaj V
中科院分区：
文献类型：
--
作者：
Sharma N;Bhushan A;He J;Kaushal G;Bhardwaj V
胰腺导管腺癌(PDAC)是最恶性的癌症之一。缺乏有效的治疗选择和耐药性是导致PDAC患者存活率低的原因。在这项研究中，我们研究了对EGFR抑制剂erlotinib无效的胰腺癌细胞的代谢变化。我们从MiaPaCa2和AsPC1细胞系中筛选出对厄洛替尼耐药的胰腺癌细胞。埃洛替尼耐药细胞的代谢谱显示，与敏感细胞相比，糖酵解活性显著下调，糖酵解代谢产物水平降低。抗性细胞表现出参与ROS调节和核苷酸生物合成的磷酸戊糖途径(PPP)酶的高表达。增强的PPP可提高细胞内NADPH/NADP+比值，保护细胞免受ROS的损伤。用6-氨基烟酰胺(6AN)抑制PPP可提高ROS水平，诱导G1期细胞周期停滞，并使耐药细胞对厄洛替尼敏感。遗传学研究证实PPP酶葡萄糖-6-磷酸脱氢酶(G6PD)升高是导致厄洛替尼耐药的重要因素。从机制上讲，我们的数据表明，分化抑制因子(ID1)的上调调节耐药细胞中G6PD的表达，从而导致代谢表型改变和对厄洛替尼的反应降低。总之，我们的结果强调了肿瘤代谢在PDAC药物反应中的潜在作用，并将G6PD确定为克服耐药性的靶点。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.
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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
肿瘤细胞代谢的修饰调节对CHK1抑制剂诱导的DNA损伤的敏感性。
影响因子：
4.6
作者：
Massey AJ
通讯作者：
Massey AJ
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
3.7
作者：
Kim, Dong Joon;Park, Young Soo;Yeom, Young Ii
通讯作者：
Yeom, Young Ii
影响因子：
11.8
作者：
Murakami, Shigekazu;Nemazanyy, Ivan;Yi, Chunling
通讯作者：
Yi, Chunling