Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment

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Abstract
There is laboratory evidence from in vitro and animal studies to suggest that antioxidants may suppress the development of cancer, though there is little conclusive evidence as to their effect in clinical conditions. Nevertheless it comes as something of a surprise to find that in certain conditions antioxidants can help promote cancer cell survival and proliferation. Normal epithelial cells die if they become detached from the structurally supportive extracellular matrix, but in breast cancer, cancer-causing genes such as ERBB2 can provide survival signals to detached tumorigenic cells. Schafer et al. show that cell detachment also causes metabolic defects that can be rescued both by ERBB2 and by antioxidants, which appear to act by boosting cellular energy levels via fatty acid oxidation. The findings point to novel mechanisms that could be exploited by cancer cells to enhance their survival in altered matrix environments. Normal mammary epithelial cells require attachment to the extracellular matrix (ECM) for survival, but in breast cancers tumour cells acquire the ability to survive outside their natural ECM niches. Here it is found that cell detachment induces metabolic defects which can be rescued by both the expression of the oncogene ERBB2 and — unexpectedly — by antioxidants, which, in this context, help promote cancer cell survival and proliferation. 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 independence1. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment2, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells3,4. 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.