Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis.

代谢失调是人类癌症的标志，在胰导管腺癌（PDAC）中糖酵解和谷氨酰胺代谢途径被证明失调。为了确定PDAC肿瘤生长和转移的新的代谢调节剂，我们使用短发夹RNA系统性地敲除了在人PDAC肿瘤样品中过表达的代谢基因。我们发现p53转录抑制对氧磷酶2（PON2），它通过胃抑素调节GLUT1介导的葡萄糖转运。PON2的丢失会引发细胞饥饿反应并激活AMP激活的蛋白激酶（AMPK）。反过来，AMPK激活FOXO3A及其转录靶标PUMA，后者诱导失神经抑制PDAC肿瘤的生长和转移。类似于PON2抑制，AMPK的药理或遗传激活可阻断PDAC肿瘤的生长。总的来说，我们的研究结果确定PON2是一种新的葡萄糖转运调节剂，可调节PDAC肿瘤生长和转移所必需的药理学上可操作的途径。