SGK-1 as a Regulator of Metabolism and Survival of ECM-Detached Cells

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 (namely loss of glucose uptake and ATP generation) that compromise cell survival. However, the precise signaling pathways utilized by cancer cells to overcome anoikis and promote ATP generation remain poorly understood. One way cancer cells can overcome anoikis and promote productive metabolism is through activating oncogenes, such as Ras. We discovered that oncogenic Ras uses divergent downstream effectors to overcome anoikis (through PHLPP1/p38 signaling) and promote glucose-mediated ATP generation (via PI(3)K/SGK-1) to facilitate survival during ECM-detachment. Given the novelty of discovery of SGK-1-mediated ATP generation (through promoting glucose uptake) specifically during detachment, as well as the ever-increasing evidence for the importance of SGK-1 in promoting tumorigenesis, we have expanded these studies and found that SGK-1 signaling is required in a variety of cell types and oncogenic backgrounds for ATP generation and survival during detachment. When examining the mechanism by which SGK-1 promotes ATP generation, we surprisingly found that treatment with the mitochondrial uncoupler CCCP did not impact the ability of SGK-1 to promote ATP generation suggesting that the TCA cycle is not required for SGK-1-mediated ATP generation. Intriguingly, ATP generation instead requires flux through the pentose phosphate pathway (PPP) and consequent production of glyceraldehyde-3-phosphate (G3P). PPP-derived G3P is then shuttled back to glycolysis where ATP production can robustly occur. 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 a variety of distinct cancer cell lines. Overall, our data suggest that oncogenic insults like Ras can utilize multiple downstream effectors to overcome anoikis activation, stimulate ATP generation, and promote survival during ECM-detachment. Further, our data suggest that SGK-1 may act as a master regulator of glucose metabolism and energy production during ECM-detachment that may be amenable to novel targeted therapies aimed at eliminating ECM-detached cancer cells through disruption of metabolism.