Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA.
Center for Informatics, City of Hope, Duarte, CA, 91010, USA.
Nat Commun. 2019 Feb 18;10(1):809. doi: 10.1038/s41467-019-08759-0.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.
胰腺导管腺癌（PDAC）是人类最致命的癌症之一。它在营养贫瘠的环境中茁壮成长；然而，PDAC 细胞如何进行代谢重编程以适应代谢应激的机制仍知之甚少。在这里，我们表明，与相邻正常组织相比，PDAC 患者样本中的 microRNA-135 显著增加。从机制上讲，miR-135 特异性地在谷氨酰胺缺乏时积累，并需要 ROS 依赖的突变 p53 的激活，这直接促进了 miR-135 的表达。从功能上讲，我们发现 miR-135 靶向磷酸果糖激酶-1（PFK1）并抑制有氧糖酵解，从而促进葡萄糖的利用以支持三羧酸（TCA）循环。一致地，miR-135 沉默使 PDAC 细胞对谷氨酰胺缺乏敏感，并抑制体内肿瘤生长。总之，这些结果确定了 PDAC 细胞在营养贫瘠的肿瘤微环境中存活的一种机制，并提供了有关突变 p53 和 miRNA 在胰腺癌细胞适应代谢应激方面的作用的见解。
