Inhibition of MAOA suppresses intracrine androgen biosynthesis and enhances abiraterone treatment in castration-resistant prostate cancer

Background: Androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enz) and abiraterone (Abi), have become cornerstone treatments for castration-resistant prostate cancer (CRPC). Despite initial favorable responses, tumors often develop resistance to these agents, partly due to activation of intracrine androgen biosynthesis, underscoring the need for effective strategies to overcome resistance and prolong the utility of ARSIs. This study investigates the role of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamines and has recently been implicated in prostate cancer, in intracrine androgen biosynthesis, and assesses the potential of MAOA inhibitors to improve Abi efficacy, an ARSI that blocks androgen biosynthesis. Methods: Multiple ARSI-resistant CRPC models were used, including C4-2B EnzR, VCaP EnzR, and C4-2B AbiR cell lines, as well as LuCaP147CR EnzR and AbiR patient-derived xenograft (PDX) models. Western blot and qPCR were used to analyze the expression of key steroidogenic enzymes involved in androgen biosynthesis in control and MAOA-knockdown cell lines. ELISA and mass spectrometry were used to measure testosterone and dihydrotestosterone (DHT) levels in cell conditioned media. Cell viability, colony formation, and in vivo tumorigenesis assays were used to evaluate the effects of MAOA inactivation by gene silencing or pharmacological approaches, combined with Abi, in both Abi-sensitive and -resistant CRPC models, including cell lines, PDX-derived organoids, and tumor xenografts. Results: The ARSI-resistant CRPC cells and PDXs showed increased expression levels of MAOA and select steroidogenic enzymes, including CYP17A1 and AKR1C3, compared to their sensitive counterparts. Silencing MAOA reduced the protein expression of CYP17A1 and AKR1C3, in EnzR and AbiR cells, likely through TWSIT1, a known MAOA downstream effector that mediates MAOA's multifaceted functions in prostate cancer. MAOA knockdown also decreased testosterone and DHT levels, both with and without the androgen precursor androstenedione, in EnzR and AbiR cells. Further, antagonizing MAOA with gene silencing or pharmacological inhibitors, including clorgyline and phenelzine, enhanced Abi effectiveness in Abi-sensitive cells and restored Abi sensitivity in resistant cells both in vitro and in vivo. Conclusion: Our findings reveal that MAOA is essential for maintaining intracrine androgen biosynthesis associated with ARSI resistance and suggest that MAOA inhibitors could enhance Abi treatment in CRPC. Funding Acknowledgements: This work was supported by NIH/NCI grants R37CA233658, R01CA258634, and R01CA279528 to BJW.