SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells.

Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake because of elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data show SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.

Ras-ling with new therapeutic targets for metastasis.

Successful cancer metastasis relies on the ability of cancer cells to survive independently of attachment to the extracellular matrix (ECM) and to overcome ECM-detachment-induced death programs. This can be accomplished through activating mutations in cellular oncogenes that subsequently lead to the inhibition of anoikis and to alterations in productive metabolism. One example of such an oncogene is Ras which is found to be mutated and hyperactivated in a variety of distinct cancers. Despite numerous studies on Ras, the precise molecular mechanisms that facilitate survival during ECM-detachment remain poorly understood. Recently, we discovered that ECM-detached cells harboring oncogenic Ras mutations require signaling through the PI(3)K/SGK1 signaling axis to promote survival. Furthermore, we found that oncogenic Ras can concurrently diminish PHLPP1 phosphatase levels, which results in a decrease in p38 MAPK-mediated activation of anoikis. Thus, our data suggest that cancer cells with activating Ras mutations can survive during ECM-detachment using downstream effector molecules that modulate distinct pathways. Overall, these data suggest that new therapeutic interventions that aim to mitigate SGK1 signaling and activate the p38 MAPK activity may aid in specifically targeting and eliminating metastatic cancer cells.

RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells.

For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH production in the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.

Metabolism during ECM Detachment: Achilles Heel of Cancer Cells?

Integrin-mediated attachment to the extracellular matrix (ECM) is required to combat the induction of programmed cell death in a variety of distinct cell types. If cells fail to maintain proper ECM attachment, they become subject to elimination via an apoptotic cell death program known as anoikis. However, anoikis inhibition is not sufficient to promote the long-term survival of ECM-detached cells. Several recent studies have unveiled the profound (anoikis-independent) impact of cell metabolism on the viability of ECM-detached cells. Thus, we posit that, during metastatic dissemination (when cancer cells are exposed to periods of ECM detachment), cancer cells must alter their metabolism in a fashion that promotes survival and ultimately contributes to metastatic outgrowth.