MYC Is a Regulator of Androgen Receptor Inhibition-Induced Metabolic Requirements in Prostate Cancer - Beyond the Abstract
Looking more into the literature and talking with colleagues, it seemed that prostate cancer could benefit from the expertise of these mitochondrial biologists. With seed funding from the UCLA Specialized Programs of Research Excellence (SPORE) in prostate cancer, we were able to get both Dr. Shirihai and Dr. Divakaruni interested in this disease.
Together, we started to look closely at how mitochondrial metabolism changes in prostate cancer cells after androgen receptor (AR) inhibition. We found two very striking phenotypes. First, we used the Seahorse assay to understand the bioenergetics, demonstrating that while glycolytic activity is reduced following antiandrogen treatment, the capacity for mitochondrial oxidative metabolism is enhanced. Second, we found a dramatic change in mitochondrial morphology when we looked closely under the microscope. Most prostate cancer cells exhibit a balance between mitochondrial fusion and fission. After using confocal microscopy and quantitative imaging analysis software, we found a statistically significant increase in mitochondrial elongation and branching after AR inhibition. Taken together, these results suggest a treatment-induced shift from glycolysis towards oxidative phosphorylation. In fact, these cells are more sensitive to inhibitors of oxidative phosphorylation after treatment, consistent with published literature.
We went on to look deeper into the mechanisms involved in this treatment-induced metabolic shift and enhanced sensitivity to complex I inhibition. We found two culprits that appear to be linked: MYC and phosphorylated DRP1. First, we wanted to understand what makes the mitochondria more elongated after treatment. Other groups had reported that DRP1, which regulates mitochondrial fission, was activated by AR, suggesting its levels might drop upon AR inhibition. Surprisingly, we saw that overall levels of DRP1 did not correlate well with AR activity. Since DRP1 phosphorylation (at S616) controls its activity, we were excited to find reduced phosphorylation after treatment. When we rescued phosphorylated DRP1, we could reverse the mitochondrial elongation phenotype (enhancing mitochondrial fission) and lower sensitivity to complex I inhibition.
MYC was the final piece of the puzzle. We wanted to understand the shift from glycolysis to reliance on mitochondrial oxidative metabolism. The glycolytic enzyme with the most consistently reduced expression after AR inhibition, in experimental models and patient samples, was hexokinase 2 (HK2). We tried and failed to rescue the phenotype by restoring HK2 expression, so we decided to look at MYC, which regulates HK2 and other glycolytic enzymes. MYC was down after treatment in experimental models and clinical samples, and rescuing MYC effectively reversed all of the AR inhibition-induced phenotypes, including the switch from glycolysis to mitochondrial oxidation, and the phosphorylation of DRP1. Most notably, rescuing MYC completely prevented treatment-induced sensitivity to complex I inhibition.
Overall, this work helps us understand how cells are metabolically responding to AR inhibition, and what regulates their treatment-induced vulnerabilities. In terms of clinical relevance, looking at how patient tumors metabolically respond to antiandrogens may provide greater insight into combination therapies that are likely to be effective. We recently began a Department of Defense-funded project to expand on this work and use positron emission tomography to better track the metabolic shift in vivo.
I am very grateful for the large number of collaborators across UCLA, Fred Hutchinson Cancer Research Center, University of British Columbia, and MD Anderson Cancer Center that helped us execute the study, including the two experts in mitochondrial biology who inspired the project. We will continue seeking out passionate scientists who can bring unique perspectives and approaches to tackle prostate cancer.
Written by: Andrew S. Goldstein, PhD, Associate Professor and Vice Chair of Undergraduate Education, Department of Molecular, Cell & Developmental Biology, Chair, Biomedical Research Minor, Associate Professor, Department of Urology, David Geffen School of Medicine, University of California, Los Angeles
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