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Principal Investigator: David Gius
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $144,601
Funding agency: National Cancer Institute
SUMMARY
The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an
established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism
leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that
disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype.
In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit
increased ROS levels and a high risk of recurrence due to endocrine therapy, has been identified.
We recently found a novel mitochondrial signaling axis centered on manganese superoxide
dismutase (MnSOD), which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts
cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast
cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2α
(known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell
biomarkers), leading to oncogenicity and pan resistance phenotype (PanR) to agents commonly
used in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumors
to exhibit a lineage plasticity phenotype. Based on our new data, our recent publication (Zhu et al,
Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology,
due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial
metabolism. This initiates metabolic reprogramming, via increased levels of HIF2α, leading to a cell
stemness-mediated tumor-permissive and/or PanR phenotype. Thus, we seek to further explore how
MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to
oncogenicity and/or PanR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic,
reverse the oncogenic and/or PanR phenotypes?
Terms: <14-Hydroxydaunomycin><Acetylation><Active Oxygen><Adjuvant Therapy><Adriamycine><Biological Markers><Biology><Breast Cancer><Breast Cancer Cell><Breast Neoplasms><Breast Tumors><CDDP><CRISPR><CRISPR/Cas system><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><ChIP Sequencing><ChIP-seq><ChIPseq><Chemicals><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clustered Regularly Interspaced Short Palindromic Repeats><Compensation><Cysplatyna><Data><Dichlorodiammineplatinum><Doxorubicin><Doxorubicina><Drug Metabolic Detoxication><Drug Metabolic Detoxification><ER Positive><ER+><Endocrine><Endocrine Therapy><Equilibrium><Estrogen receptor positive><Event><Exhibits><Exposure to><Faslodex><Fats><Fatty acid glycerol esters><Fulvestrant><Genes><Hemi-Myeloperoxidase><Hormonal Therapy><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><ICI 182,780><ICI 182780><IPO-B><Indophenol Oxidase B><Intermediary Metabolism><Intracellular Communication and Signaling><Knock-out><Knockout><L-Lysine><Lead><Link><Lysine><MCF-7><MCF-7 Cell><MCF-7DR><MCF-7WT><MCF7><MCF7 cell><MNSOD><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Manganese Superoxide Dismutase><Measurement><Measures><Mediating><Metabolic><Metabolic Drug Detoxications><Metabolic Processes><Metabolism><Metabolism of Toxic Agents><Mitochondria><Mitochondrial Superoxide Dismutase><Mn Superoxide Dismutase><Mn-SOD><Modeling><Myeloperoxidase><Nature><Oncogenesis><Oncogenic><Oxygen Radicals><PDX model><Pathway interactions><Patient derived xenograft><Pb element><Peroxidases><Peyrone's Chloride><Peyrone's Salt><Phenotype><Physiologic><Physiological><Platinum Diamminodichloride><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Pro-Oxidants><Property><Protein Modification><Publications><RNA Seq><RNA sequencing><RNAseq><Reactive Oxygen Species><Recurrence><Recurrent><Reporter><Resistance><Risk><SERMs><SOD2><SOD2 gene><SYS-TX><Scientific Publication><Selective Estrogen Receptor Modulators><Signal Transduction><Signal Transduction Systems><Signaling><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuins><Staining method><Stains><Stem Cell like><Subcellular Process><Subgroup><Superoxide Anion><Superoxide Dismutase 2><Superoxide Radical><Superoxides><Systemic Therapy><T-47D><T47D><Tamoxifen><Techniques><Testing><Time><Tissue Arrays><Tissue Chip><Tissue Microarray><Tumor Cell><Tumor Promoters><Woman><Work><Xenograft Model><adjuvant treatment><balance><balance function><bio-markers><biologic marker><biological signal transduction><biomarker><breast malignancies><breast tumor cell><cancer cell><cell metabolism><cellular metabaolism><chromatin immunoprecipitation-sequencing><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><detoxification><heavy metal Pb><heavy metal lead><high risk><hormone therapy><in vivo><knock-down><knockdown><malignancy><malignant breast tumor><mammary><mammary tumor><mimetics><mitochondrial><mitochondrial metabolism><monomer><mouse model><murine model><mutant><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><patient derived xenograft model><permissiveness><prevent><preventing><progenitor cell markers><progenitor markers><progenitor stem cell markers><progenitor-like cell><programs><public data base><public database><publicly accessible data base><publicly accessible database><publicly available data base><publicly available database><resistance to therapy><resistant><resistant to therapy><response><shRNA><short hairpin RNA><small hairpin RNA><stem><stem cell biomarkers><stem cell characteristics><stem cell markers><stem-like cell><stemness><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><tissue culture><transcriptome sequencing><transcriptomic sequencing><treatment resistance><tumor><tumorigenesis><tumorigenic><xenograft transplant model><xenotransplant model>