Abstract
BackgroundHypoxic microenvironments in tumors contribute to transformation, which may alter metabolism, growth, and therapeutic responsiveness. The α-enolase gene encodes both a glycolytic enzyme (α-enolase) and a DNA-binding tumor suppressor protein, c-myc binding protein (MBP-1). These divergent α-enolase gene products play central roles in glucose metabolism and growth regulation and their differential regulation may be critical for tumor adaptation to hypoxia. We have previously shown that MBP-1 and its binding to the c-myc P2 promoter regulates the metabolic and cellular growth changes that occur in response to altered exogenous glucose concentrations.ResultsTo examine the regulation of α-enolase and MBP-1 by a hypoxic microenvironment in breast cancer, MCF-7 cells were grown in low, physiologic, or high glucose under 1% oxygen. Our results demonstrate that adaptation to hypoxia involves attenuation of MBP-1 translation and loss of MBP-1-mediated regulation of c-myc transcription, evidenced by decreased MBP-1 binding to the c-myc P2 promoter. This allows for a robust increase in c-myc expression, "early c-myc response", which stimulates aerobic glycolysis resulting in tumor acclimation to oxidative stress. Increased α-enolase mRNA and preferential translation/post-translational modification may also allow for acclimatization to low oxygen, particularly under low glucose concentrations.ConclusionsThese results demonstrate that malignant cells adapt to hypoxia by modulating α-enolase/MBP-1 levels and suggest a mechanism for tumor cell induction of the hyperglycolytic state. This important "feedback" mechanism may help transformed cells to escape the apoptotic cascade, allowing for survival during limited glucose and oxygen availability.
Highlights
Hypoxic microenvironments in tumors contribute to transformation, which may alter metabolism, growth, and therapeutic responsiveness
This study provides a new mechanism for the regulation of cell growth and metabolism of transformed cells under hypoxia, demonstrating that induction of α-enolase mRNA, preferential translation of α-enolase over c-myc binding protein (MBP-1), and inhibition of MBP-1 function may all be involved in both promoting survival of human breast carcinoma cells (MCF-7) cells and stimulating cell growth under substrate limitation
After 6 h of hypoxia, cell number increased modestly in MCF-7 cells grown in 5 mM and 25 mM glucose and the increase was maintained through 48 h (Fig. 1B)
Summary
Hypoxic microenvironments in tumors contribute to transformation, which may alter metabolism, growth, and therapeutic responsiveness. As a result of variable blood flow (oxygen supply) and rapid utilization of glucose within solid tumors (oxygen utilization), most tumor cells are subjected to a microenvironment that is hypoxic and may be hypoglycemic. These conditions likely contribute to tumor transformation and growth [3,4]. Transformed cells demonstrate increased levels of glycolysis, which are associated with increased levels of glycolytic enzyme mRNA and protein [59] This results in the production of, large amounts of lactic acid (Warburg Effect) [10,11]. The changes associated with increased glycolytic enzyme mRNA and protein levels [5,9] have been well documented, the exact mechanisms leading to increased glycolysis and abnormal tumor cell growth under hypoxic conditions are not completely understood
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