The Role of Multicellular Aggregation in the Survival of ErbB2-positive Breast Cancer Cells during Extracellular Matrix Detachment

Rayavarapu, Raju R.; Heiden, Brendan T.; Pagani, Nicholas; Shaw, Melissa; Shuff, Sydney; Zhang, Siyuan; Schafer, Zachary T.

doi:10.1074/jbc.m114.612754

Cited by 38 publications

(29 citation statements)

References 53 publications

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“…Since anoikis prevents anchorage-independent proliferation and attachment to an improper matrix, it is generally considered as an oncosuppressive process [ 234 , 236 ]. Accordingly, cancer cells need to acquire at least some degree of resistance to anoikis to initiate and progress though the so-called “metastatic cascade” [ 237 – 239 ]. Neoplastic cells can evade anoikis upon activation of mitogen-activated protein kinase 1 (MAPK1; best known as ERK2) caused by cellular aggregation and consequent epidermal growth factor receptor (EGFR) stabilization mediated by erb-b2 receptor tyrosine kinase 2 (ERBB2) [ 237 , 240 ], or degradation of the negative ERK2 regulator BRCA1-associated protein (BRAP), which is favored by coiled-coil domain containing 178 (CCDC178) [ 241 ].…”

Section: Intrinsic Apoptosismentioning

confidence: 99%

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

et al. 2018

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Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

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Section: Intrinsic Apoptosismentioning

confidence: 99%

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

et al. 2018

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“…6 These data suggest that the strategies used by cancer cells to alleviate deleterious metabolic changes (and block anoikis) may vary considerably across tumor types and contexts. 11,29,30 Additional studies examining the relationship between oncogenic signaling and metabolism in ECM-detached cancer cells are warranted to better ascertain the best strategies to facilitate their elimination.…”

Section: Discussionmentioning

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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“…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.…”

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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The Role of Multicellular Aggregation in the Survival of ErbB2-positive Breast Cancer Cells during Extracellular Matrix Detachment

Cited by 38 publications

References 53 publications

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

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

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

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