Antioxidant and Oncogene Rescue of Metabolic Defects Caused by Loss of Matrix Attachment

By Z. Schafer, A. Grassian, L. Song, Zhe‐Yu Jiang, Zachary Gerhart-Hines, H. Irie, Sizhen Gao, P. Puigserver, J. Brugge. Nature, 2009

1,013 citations recorded by the source corpus.

Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3)K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/00ad2a6b8b2753f0b699001a3f579b45e92f4fdf

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Citations in the corpus

Understanding the intersections between metabolism and cancer biology (2017, neutral): “In breast epithelial cells, loss of matrix attachment results in oxidative stress and cell death (Schafer et al., 2009).”
Oxidative Stress in Cancer (2020, background): “Indeed, detachment of non-transformed human MCF-10A breast epithelial cells increases ROS and decreases GSH due to diminished PPP flux (Schafer et al., 2009), while detachment of human A549 non-small cell lung cancer cells increases H2O2 and decreases NADPH levels (Jeon et al.”
The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism (2014, background): “In fact, cell detachment causes dramatic global metabolic changes characterized by reduced uptake of nutrients (including glucose) and consequently decreased glycolysis and the TCA cycle [35] [39] [36].”
Lactate: a metabolic key player in cancer. (2011, background): “Findings of Schafer and colleagues (11) showed that upregulation of glycolysis in detached Her2/neuþ ductal breast cancer cells could provide them with a survival”
Role of Glutathione in Cancer: From Mechanisms to Therapies (2020, background): “This may be related to the findings that high levels of ROS can mitigate metastasis and tumorigenesis, for example in cancer cells detaching from the extracellular matrix [42,43].”
Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, neutral): “Some of the signaling events that oversee anoikis responses impinge upon metabolic programs, such as the pentose phosphate pathway and control of glucose uptake (Schafer et al., 2009).”
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway (2014, background): “Subsequently, it was found that oxidative stress is induced upon matrix detachment of cells and that resistance against detachment-induced cell death (anoikis) largely depends on antioxidant capacity (Schafer et al., 2009).”
Metabolic reprogramming and cancer progression (2020, background): “This pathway provides reducing equivalents to regenerate ROS-detoxifying metabolites, such as glutathione (74).”
A global perspective on carotenoids: Metabolism, biotechnology, and benefits for nutrition and health. (2018, background): “It might be added that reduction of ROS by antioxidants can lead to the survival of preinitiated tumor cells [423].”