Prostate cancer, the leading cause of cancer-related death among non-smoking males in the United States, often progresses from localized to advanced metastatic disease due to aberrant androgen receptor (AR) activity. The current treatment strategy involves androgen deprivation therapy (ADT) to suppress AR activity, which initially shows efficacy but eventually leads to tumor recurrence. In a new study published in the peer-reviewed Journal Cell Reports and led by Assistant Professor Andrew Goldstein from the Department of Molecular, Cell, and Developmental Biology at the University of California, Los Angeles, researchers aimed to understand how prostate cancer cells reprogram their metabolism in response to AR blockade, a phenomenon crucial for understanding cancer progression and resistance to therapy. Researchers employed transcriptomic and metabolomic profiling to investigate metabolic changes following clinical AR blockade. They used the 16D castration-resistant prostate cancer (CRPC) cell line, treated with enzalutamide (an AR inhibitor), to model these changes. This approach allowed the identification of key metabolic pathways altered by AR inhibition, particularly those related to oxidative phosphorylation and glycolysis.
The research team used transcriptomic and metabolomic profiling to assess the changes in metabolic pathways after AR blockade in prostate cancer cells. The 16D castration-resistant prostate cancer (CRPC) cell line was treated with enzalutamide, an AR inhibitor, to simulate the effects of AR blockade. They conducted assays to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in cells treated with enzalutamide, assessing changes in their bioenergetics. The authors also examined the effect of AR inhibition on mitochondrial morphology and dynamics, particularly focusing on the role of DRP1, a protein involved in mitochondrial fission. Additionally, the researchers looked into the expression of glycolytic enzymes and MYC signaling, important regulators of cancer cell metabolism, in response to AR inhibition.
The team found that AR inhibition led to a shift in the metabolic profile of prostate cancer cells, characterized by an increased reliance on oxidative mitochondrial metabolism and a reduction in glycolysis. The authors demonstrated that Enzalutamide-treated cells displayed increased sensitivity to complex I inhibitors, suggesting a heightened dependence on oxidative phosphorylation for energy production. Post-AR inhibition, the cells exhibited elongated mitochondria, a change linked to the reduced activity of the DRP1 protein. The study revealed a significant reduction in MYC signaling following AR inhibition. Furthermore, reactivation of MYC in these cells reversed the reduction in glycolysis and restored mitochondrial dynamics, highlighting MYC’s crucial role in metabolic adaptation. Sustained MYC expression during enzalutamide treatment was found to confer resistance to AR inhibition by maintaining glycolytic metabolism, pointing to potential mechanisms behind treatment resistance in prostate cancer.
The team showed that AR inhibition led to significant metabolic reprogramming in prostate cancer cells. Post AR-blockade, cells showed an increased reliance on oxidative mitochondrial metabolism, coupled with reduced glycolysis. Bioenergetic assays measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) indicated that while ATP-linked respiration was not significantly altered, there was an enhancement in the maximal capacity for oxidative mitochondrial metabolism. A notable finding was the increased sensitivity of enzalutamide-treated cells to complex I inhibitors. This was evident through respirometry and tracer analyses, which showed a dramatic reduction in ATP-linked respiration and changes in metabolic profiles following treatment with complex I inhibitors. This suggested a shift in the cells’ metabolic dependencies, increasing their vulnerability to metabolic inhibitors.
The authors findings also shed light on changes in mitochondrial dynamics due to AR blockade. Enzalutamide-treated cells exhibited elongated mitochondria, a change regulated by the phosphorylation of DRP1, a protein involved in mitochondrial fission. The altered mitochondrial morphology was likely a response to cellular and environmental stresses induced by AR inhibition. A key discovery was the downregulation of glycolytic enzymes like Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA) in cells post AR inhibition. This downregulation contributed to reduced glycolysis. Additionally, reduced MYC signaling was identified as a significant factor mediating these metabolic changes. The study found that ectopic MYC expression could reverse the reduction in glycolytic activity and restore mitochondrial dynamics, indicating the central role of MYC in regulating metabolic responses to AR inhibition. Furthermore, the study hypothesized and demonstrated that sustained MYC expression during enzalutamide treatment could confer resistance to AR inhibition by maintaining glycolysis. This was supported by data showing that MYC expression mitigated enzalutamide-induced metabolic changes and increased drug resistance in prostate cancer cells. The researchers comprehensively elucidated the metabolic effects of AR blockade in prostate cancer, highlighting the shift towards oxidative mitochondrial metabolism and the associated sensitivity to complex I inhibition. It underscored the roles of altered mitochondrial dynamics and MYC signaling in these processes. These findings suggest a potential therapeutic window for targeting mitochondrial metabolism following AR inhibition, though further research is needed to fully understand the implications and develop effective, patient-specific treatments.
The in-depth analysis of the metabolic reprogramming in prostate cancer following AR inhibition underscores the complexity and adaptability of cancer metabolism, presenting new avenues for therapeutic intervention and a deeper understanding of treatment resistance mechanisms. In summary, the Professor Goldstein and colleagues provided a detailed insight into the metabolic alterations occurring in prostate cancer cells due to AR inhibition, revealing the complex interplay between metabolic pathways, mitochondrial dynamics, and cancer cell survival and resistance mechanisms.
Crowell PD, Giafaglione JM, Jones AE, Nunley NM, Hashimoto T, Delcourt AML, Petcherski A, Agrawal R, Bernard MJ, Diaz JA, Heering KY, Huang RR, Low JY, Matulionis N, Navone NM, Ye H, Zoubeidi A, Christofk HR, Rettig MB, Reiter RE, Haffner MC, Boutros PC, Shirihai OS, Divakaruni AS, Goldstein AS. MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer. Cell Rep. 2023 Oct 31;42(10):113221. doi: 10.1016/j.celrep.2023.113221.