PON2 Promotes Glucose Uptake to Support PDAC Growth and Metastasis

The glycolytic and glutamine metabolic pathways are deregulated in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying this deregulation are not well understood. Nagarajan and colleagues performed an siRNA screen of metabolic genes overexpressed in patients with PDAC to identify those essential for PDAC tumor growth. Paraoxonase 2 (PON2) was found to be required for the growth of PDAC cells in vitro and in vivo, and cooperated with KRAS^G12D to accelerate tumor progression. Further, PON2 expression prevented anoikis, to allow enhanced PDAC metastasis. Transcription of PON2 was directly repressed by the tumor suppressor p53; thus, p53 inactivation resulted in PON2 upregulation. Mechanistically, PON2 loss activated the cellular starvation response, leading to AMPK-mediated activation of the tumor suppressive transcription factor FOXO3A, and upregulation of its proapoptotic target gene PUMA, to promote anoikis and suppress PDAC growth and metastasis. Conversely, PON2 overexpression promoted glucose uptake by binding to the glucose transporter GLUT1 and blocking its interaction with the inhibitory protein STOM, thereby supporting PDAC growth and metastasis. Consistent with these findings, depletion of FOXO3A or suppression of AMPK activation could promote tumor growth in PON2-deficient cells and suppress anoikis. In a mouse model of PDAC lung metastasis, PON2 depletion could suppress the growth of established lung tumors. Moreover, the AMPK agonists metformin or AICAR inhibited PDAC colony formation and suppressed tumorigenesis in vivo. Thus, AMPK activation and PON2 inhibition have similar effects in suppressing PDAC tumor growth. The identification of PON2 as an essential regulator of GLUT1-mediated glucose transport for PDAC growth and metastasis suggests that pharmacologic activation of the AMPK–FOXO3A–PUMA pathway may be a therapeutic approach to suppress PDAC growth.

Nagarajan A, Dogra SK, Sun L, Gandotra N, Ho T, Cai G, et al. Paraoxonase 2 facilitates pancreatic cancer growth and metastasis by stimulating GLUT1-mediated glucose transport. Mol Cell 2017;67:685–701.e6.

• ©2017 American Association for Cancer Research.