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

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 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, using GC4419, which 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