Hypoxia induces differential translation of enolase/MBP-1.
BACKGROUND
Hypoxic microenvironments in tumors contribute to transformation, which may alter metabolism, growth, and therapeutic responsiveness. The alpha-enolase gene encodes both a glycolytic enzyme (alpha-enolase) and a DNA-binding tumor suppressor protein, c-myc binding protein (MBP-1). These divergent alpha-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.


RESULTS
To examine the regulation of alpha-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 alpha-enolase mRNA and preferential translation/post-translational modification may also allow for acclimatization to low oxygen, particularly under low glucose concentrations.


CONCLUSIONS
These results demonstrate that malignant cells adapt to hypoxia by modulating alpha-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.
Sedoris
Kara C
KC
James Graham Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Thomas
Shelia D
SD
Miller
Donald M
DM
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D010751:Phosphopyruvate Hydratase / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014178:Translocation, Genetic; D015854:Up-Regulation
C088830:DENND4A protein, human; D004268:DNA-Binding Proteins; D027342:Excitatory Amino Acid Transporter 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D010751:Phosphopyruvate Hydratase; D005947:Glucose