Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.
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.
Schafer
Zachary T
ZT
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Grassian
Alexandra R
AR
Song
Loling
L
Jiang
Zhenyang
Z
Gerhart-Hines
Zachary
Z
Irie
Hanna Y
HY
Gao
Sizhen
S
Puigserver
Pere
P
Brugge
Joan S
JS
D000255:Adenosine Triphosphate / Q000378:metabolism; D023102:Anoikis / Q000502:physiology; D000975:Antioxidants / Q000378:metabolism*; D001940:Breast / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
D000255:Adenosine Triphosphate; D000975:Antioxidants; D066246:ErbB Receptors; D005227:Fatty Acids; D005947:Glucose; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
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