Sharma Neha, Bhushan Alok, He Jun, Kaushal Gagan, Bhardwaj Vikas
Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA USA.
Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA.
Cancer Metab. 2020 Sep 21;8:19. doi: 10.1186/s40170-020-00226-5. eCollection 2020.
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.
胰腺导管腺癌（PDAC）是最恶性的癌症形式之一。缺乏有效的治疗选择和耐药性导致PDAC患者生存率较低。在本研究中，我们调查了对表皮生长因子受体（EGFR）抑制剂厄洛替尼无反应的胰腺癌细胞中的代谢改变。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。与敏感细胞相比，对厄洛替尼耐药细胞的代谢谱分析显示糖酵解活性显著下调，糖酵解代谢物水平降低。耐药细胞中参与活性氧（ROS）调节和核苷酸生物合成的磷酸戊糖途径（PPP）酶表达升高。增强的PPP提高了细胞内烟酰胺腺嘌呤二核苷酸磷酸（NADPH）/烟酰胺腺嘌呤二核苷酸磷酸（NADP+）比值，并保护细胞免受ROS诱导的损伤。使用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。遗传学研究确定PPP酶葡萄糖-6-磷酸脱氢酶（G6PD）表达升高是厄洛替尼耐药的重要原因。从机制上讲，我们的数据表明，分化抑制因子（ID1）的上调调节了耐药细胞中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，我们的结果突出了肿瘤代谢在PDAC药物反应中的潜在作用，并确定G6PD是克服耐药性的靶点。
