Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer

Background: Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normalprostate glands. However, the relationship between survivin and MAOA in PCa is unclear.Methods: We examined MAOA expression in the prostate lobes of a conditional PTEN-deficient mouse model mirroring humanPCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We furtherevaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCacells.Results: Survivin and MAOA levels are both increased in clinical PCa tissues and significantly associated with patients’ survival.Survivin depletion delayed MAOA increase during PCa progression, and silencing MAOA decreased survivin expression. Thecombination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition ofPCa cell growth, migration and invasion with concomitant decrease in survivin and MMP-9 levels.Conclusions: There is a positive feedback loop between survivin and MAOA expression in PCa. Considering that survivinsuppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support arapid translation of this combination to clinical practice.