Research Project 2 - Hypoxia and anaerobic metabolism regulation of cancer cell survival: a novel molecular target for anticancer therapeutics - K.F. Soliman H. Flores-Rozas, S. Darling and E. Mazzio: In the US, African Americans still continue to experience highest death rates from many different types of cancers. Often times, socioeconomic disadvantage places individuals in a compromising position of not being able to afford proper medical care thereby forgoing necessary early detection and treatment. This poses considerable challenge because a cancer can gain strength over time transforming into aggressive malignancy, which is non-responsive to chemotherapy or radiation. This evolutionary process is believed to be the result of events occurring at the core of a primary solid tumor mass. As a tumor grows, its central core becomes exposed to low p02 (hypoxia) resulting In genetic adaptations which foster expression of a diverse array of proteins that promote survival, growth, metastasis and angiogenesis. A lack of O2 prevents HIF-1 a proteosomal degradation, leading to HIF-1 a-HIF-1B dimerization and its translocation to the nucleus where hypoxic response element (HRE) genes initiate transcription of proteins that perpetuate survival. Because late stage cancers are often untreatable, the understanding of molecular, genetic or functional regulation of glucose metabolism in hypoxic tumor cells are critical in order to elucidate targeted therapeutic treatments that will destroy the tumor without harm to the host.. Our preliminary data show that hypoxic tumor cells use glucose to produce ATP in a process that appears to expand beyond the traditional """"""""Warburg"""""""" effect as previously thought. These pathways could involve cytosolic oxidation - reduction/ energy yielding reactions that are not required by the host. Second, our preliminary research indicates that the acidosis that occurs In response to a lack of O2 (i.e. lactic acid, acetate /carbonic acid) could be more important than the level of O2 concentration in regulating HIF-1 mediated events. These results pose several questions about the current held concepts regarding mechanisms that propel the aggressive nature of cancer. The goal of this research is to elucidate metabolic pathways involved In ATP production in tumor cells exposed to hypoxia, identify molecular targets and screen natural therapeutic compounds to modify these targets in order to develop effective treatments for end stage aggressive cancers. To achieve this goal, specific aims include: 1. to identify and quantify metabolic products formed by tumor cells under various models of hypoxia. 2. To identify potential gene and protein molecular targets involved with metabolic anaerobic production of ATP and to establish the integrated metabolic pathways involved. 3) To silence identified target genes in assessment of functional analytical studies and to screen natural products for efficacy in modifying molecular targets in order to shut down energy metabolism In the tumor without adverse effects to the host. Our longterm goal is to contribute toward defining the molecular and genetic basis for anaerobic survival patterns in tumor cells.
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