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 HIF2a,
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 HIF2a, 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
