Antioxidant Enzymes Mediate Survival of Breast Cancer Cells Deprived of Extracellular Matrix

Davison, Calli A.; Durbin, Sienna; Thau, Matthew R.; Zellmer, Victoria R.; Chapman, Sarah E.; Diener, Justin; Wathen, Connor; Leevy, W. Matthew; Schafer, Zachary T.

doi:10.1158/0008-5472.can-12-2482

Cited by 120 publications

(93 citation statements)

References 33 publications

(50 reference statements)

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“…Perhaps this defect could be overcome through changes in glucose or fatty acid metabolism that have previously been reported in ECM-detached cells. 24,48 Thus it will be especially important to examine metabolic changes in IBC cells to understand how these cells deal with metabolic needs during ECM detachment. Nonetheless, the data presented here provide significant and novel insight into the molecular mechanisms utilized by IBC cells to survive in the absence of ECM attachment.…”

Section: Discussionmentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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Section: Discussionmentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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“…Indeed, it was discovered that these ECMdetached mammary epithelial cells had a number of substantial metabolic alterations (e.g. deficient glucose uptake, diminished cellular ATP levels) and that rectifying these alterations, independent of modulating anoikis, could promote survival of ECM-detached cells in the luminal space of the mammary acini (17,18).…”

Section: Pentose Phosphate Pathway (Ppp)mentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Hawk

Schafer

2018

Journal of Biological Chemistry

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Abstract:Non-transformed cells that become detached from the extracellular matrix (ECM) undergo dysregulation of redox homeostasis and cell death. In contrast, cancer cells often acquire the ability to mitigate programmed cell death pathways and recalibrate the redox balance to survive after ECM detachment, facilitating metastatic dissemination. Accordingly, recent studies of the mechanisms by which cancer cells overcome ECM detachment-induced metabolic alterations have focused on mechanisms in redox homeostasis. The insights into these mechanisms may inform the development of therapeutics that manipulate redox homeostasis to eliminate ECMdetached cancer cells. Here, we review how ECM-detached cancer cells balance redox metabolism for survival. Introduction:

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“…[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.…”

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confidence: 99%

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

et al. 2016

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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...

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Antioxidant Enzymes Mediate Survival of Breast Cancer Cells Deprived of Extracellular Matrix

Cited by 120 publications

References 33 publications

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

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

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

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