Abstract 2403: SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival

Abstract

Successful metastasis requires cancer cells to overcome both anoikis -caspase dependent cell death triggered by extracellular matrix (ECM) detachment—and ECM-detachment-induced metabolic defects that compromise cell survival. While studies have begun to elucidate signal transduction cascades responsible for anoikis evasion, less is known about the precise signals cancer cells use to overcome ECM-detachment induced metabolic deficiencies. Previously, we discovered that oncogenic Ras utilizes a PI(3)K/SGK-1 signaling cascade in order to promote glucose-mediated ATP generation and survival of ECM-detached cells. We have expanded these studies and found that SGK-1 signaling is required in a variety of cell types and oncogenic backgrounds (during ECM-detachment) for glucose-derived ATP production and anchorage independent growth. Our data demonstrate that SGK-1 is required for glucose uptake due to its regulation of the GLUT1 transporter. SGK-1 appears to not only promote GLUT1 localization at the plasma membrane, but also to dramatically promote its transcription. Once inside the cell, SGK-1 promotes the flux of glucose into the glycolytic and pentose phosphate pathways (PPP). When further examining the mechanism by which SGK-1 promotes ATP generation, we surprisingly found that uncoupling the mitochondria did not impact the ability of SGK-1 to promote ATP generation. These data suggest that the TCA cycle is not required for SGK-1 mediated ATP generation. Intriguingly, ATP generation instead requires flux through the PPP and consequent production of glyceraldehyde-3-phosphate (G3P). PPP-derived G3P is shuttled back to glycolysis where ATP production robustly occurs. This metabolic pathway appears to be critical for the anchorage-independent growth of cancer cells as genetic or pharmacological disruption of glucose flux through the PPP significantly abrogates colony formation in soft agar in a variety of distinct cell lines. Overall, these data uncover a novel metabolic pathway downstream of SGK-1 that is highly conserved across multiple epithelial cancer cell lines during ECM detachment. Citation Format: Jordan A. Cockfield, Joshua A. Mason, Zachary T. Schafer. SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2403.