Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Abstract

In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. Cell Death and Differentiation (2016) 23, 1271-1282 doi:10.1038/cdd.2016 published online 26 February 2016 Cancer metastasis, the spread of cancer cells to distant parts of the body, accounts for~90% of cancer-related deaths and represents an inherently difficult clinical challenge.1,2 It has become clear that for successful metastasis to occur, cells must overcome a caspase-dependent cell death mechanism, anoikis, which is triggered by detachment from the extracellular matrix (ECM).3 In addition to anoikis evasion, cancer cells must also contend with anoikis-independent cellular alterations that can compromise cellular viability. 4 Chief among these alterations are metabolic deficiencies that are induced by ECM detachment. [5][6][7] These metabolic alterations involve deficiencies in ATP generation, elevated levels of reactive oxygen species, and the induction of autophagy. 6,8,9 Although recent studies have begun to unravel the strategies used by cancer cells to ameliorate metabolic deficiencies during ECM detachment, 10 the signal-transduction cascades responsible for regulating metabolism during ECM detachment in cancer cells remain almost entirely unexplored.The activation of oncogenic signaling pathways is critical to anchorage-independent growth and ultimately to the survival of a variety of distinct cancer cell types during ECM detachment. 4,11 Presumably, this oncogenic signaling is also necessary for resolving the aforementioned ECM-detachment-induced metabolic deficiencies. ErbB2 overexpression in mammary epithelial cells results in a stimulation of phosphatidylinositol (3)-kinase (PI(3)K)/Akt signaling to promote glucose uptake and ATP generation.6 These data raise the question as to how cancer cells that lack ErbB2 overexpression rectify metabolic deficiencies during ECM detachment. Does activation o...

Cancer metabolism in space and time: Beyond the Warburg effect

“…ATP gen er a tion) in ad di tion to block ing anoikis in or der to sur vive to de tach ment from the ex tra cel lu lar ma trix [9]. Both stim u la tion of ATP pro duc tion and anoikis in hi bi tion are reg u lated by a sim i lar sig nal ing path way op er at ing down stream of onco genic Ras by ac ti va tion of AKT and serum and glu co cor ti coid reg u lated ki nase 1 (SGK 1) [142].…”

Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment

“…Oftentimes, these modifications in survival signaling converge on the Bcl-2 family of proteins which modulate the release of cytochrome c from the intermembrane space. Multiple signaling pathways regulating mitochondrial permeabilization during anoikis have been unveiled in numerous and disparate contexts (5)(6)(7)(8)(9)(10)(11)(12). A fundamental implication of these findings is that cancer cells can employ a multi-faceted arsenal of diverse and overlapping strategies to block anoikis induction leading to their survival.…”

“…Additionally, ECM-detachment is now well established to cause a host of catastrophic metabolic alterations including defective glucose uptake, diminished pentose phosphate pathway (PPP) flux, reduced cellular ATP levels, and a robust increase in reactive oxygen species (ROS) (7,17,18). This elevated ROS during ECMdetachment and the consequences on the viability of cells is now an area of dynamic investigation in a number of different contexts.…”

SGK-1 and PHLPP1: Ras-mediated effectors during ECM-detachment

“…1). 5 Here, we discuss these findings in more detail and how this information may be exploited to design novel therapeutic strategies that can eliminate metastatic cancer cells.…”

“…In support of this, we discovered that constitutive activation of Ras (either H-Ras and K-Ras) has the capacity to promote ATP generation and subsequent survival during ECM-detachment by increasing glucose uptake. 5 This Ras-mediated promotion of ATP generation is mediated by phosphatidylinositol 3-kinase (PI3K), but surprisingly, does not require Akt activation. Instead, we find that the kinase activity of serum and glucocorticoid kinase-1 (SGK-1) is necessary for Ras-mediated glucose uptake, ATP generation, and survival during ECM-detachment.…”