Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

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SUMMARY The overarching goal of this new R01 application is to investigate the dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer. This disruption of cellular metabolism, leads to the aberrant accumulation of reactive oxygen species (ROS), triggering maladaptive signaling that is an emerging, novel mechanism leading to ionizing radiation (IR) resistance (IRR) as well as enzalutamide (ENZ) resistance (ENZR). In this regard, recently identified a mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cellular metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, LNCaP cells expressing a MnSOD K68-Ac mimic mutant (MnSODK68Q) exhibited IRR/ENZR, increased HIF2α, known to promote stemness properties, and two stem cell markers, Oct4 and SOX2. As such, we seek to show that MnSOD-K68-Ac may drive IRR and/or ENZR, by altering MnSOD's structural composition and enzymatic activity, and in a broader context, tumor growth and survival via a cell stemness-like mechanism. Finally, will GC4419 exposure, a chemical agent that acts as a MnSOD mimic, reverse the IRR/ENZR phenotype? Thus, it is It is hypothesized that prostate tumor cells exposed to IRR and/or ENZR increase MnSOD-K68-Ac, disrupting normal MnSOD biology at the cellular and mitochondrial level (i.e., aberrant ROS), which initiates cellular reprogramming, via increased HIF2α, leading to lineage plasticity properties, a change in tumor cell fate, and an IRR and/or ENZR tumor phenotype. It is also proposed that MnSOD-K68-Ac is a novel axis for new therapeutic interventions in IRR and IRR/ENZR tumors. Finally, through exposure to GC4419 that chemically replaces MnSOD activity, we ask whether superoxide detoxification reverts/converts these IRR/ENZR prostate tumor cells to a sensitive phenotype by restoring normal metabolism