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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD006738-03
Application #
8611735
Study Section
Special Emphasis Panel (ZMD1-RN)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$145,024
Indirect Cost
$38,281
Name
Florida Agricultural and Mechanical University
Department
Type
DUNS #
623751831
City
Tallahassee
State
FL
Country
United States
Zip Code
32307
Badisa, Ramesh B; Wi, Sungsool; Jones, Zachary et al. (2018) Cellular and molecular responses to acute cocaine treatment in neuronal-like N2a cells: potential mechanism for its resistance in cell death. Cell Death Discov 4:13
Miles, Jana S; Sojourner, Samantha J; Whitmore, Aurellia M et al. (2018) Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast. Biomed Res Int 2018:4938189
Mazzio, Elizabeth A; Lewis, Charles A; Elhag, Rashid et al. (2018) Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response. Cancer Genomics Proteomics 15:249-264
Miles, Jana S; Sojourner, Samantha J; Jaafar, Lahcen et al. (2018) THE ROLE OF PROTEIN CHAPERONES IN THE SURVIVAL FROM ANTHRACYCLINE-INDUCED OXIDATIVE STRESS IN SACCHAROMYCES CEREVISIAE. Int J Adv Res (Indore) 6:144-152
Mazzio, Elizabeth A; Soliman, Karam F A (2018) Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A. Cancer Genomics Proteomics 15:349-364
Cheriyan, Vino T; Alsaab, Hashem; Sekhar, Sreeja et al. (2018) A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers. Oncotarget 9:29680-29697
Badisa, Ramesh B; Batton, Chyree S; Mazzio, Elizabeth et al. (2018) Identification of biochemical and cytotoxic markers in cocaine treated PC12 cells. Sci Rep 8:2710
Cobourne-Duval, Makini K; Taka, Equar; Mendonca, Patricia et al. (2018) Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NF?B pathway signaling targets in LPS/IFN? -activated BV-2 microglia cells. J Neuroimmunol 320:87-97
Sojourner, Samantha J; Graham, Willie M; Whitmore, Aurellia M et al. (2018) The Role of HSP40 Conserved Motifs in the Response to Cytotoxic Stress. J Nat Sci 4:
Mazzio, E; Badisa, R; Eyunni, S et al. (2018) Bioactivity-Guided Isolation of Neuritogenic Factor from the Seeds of the Gac Plant (Momordica cochinchinensis). Evid Based Complement Alternat Med 2018:8953958

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