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

Abstract

Background:Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normal prostate 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 human PCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We further evaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells.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. The combination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition of PCa 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 survivin suppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support a rapid translation of this combination to clinical practice.

Studying the Enzymes Levels in Cerebrospinal Fluid for Children With Acute Lymphoblastic Leukemia

“…MAOA activity was found to be significant increased (p<0.05) in CSF of patients with acute lymphoblastic leukemia compared with control group as shown in tables (2) and (3) in both sexes for all age groups, this result was in agreement with other reports [27,28] who found evaluated levels of MAO in prostate cancer patients.…”

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

“…Pargyline has been described to have only slight selectivity for MAO-B (Fuller & Hemrick, 1978). In contrast to MAO-A, MAO-B is expressed in normal prostate tissue and its levels are substantially reduced in PCa tissue (Xu et al, 2015).…”

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

“…MAO inhibitors may also be relevant to other conditions, and are thus under investigation as therapies for Alzheimer's disease, certain types of cancer and age-related impairment of cardiac function. In Alzheimer's disease, MAO inhibitors may reverse amyloid β peptide (Aβ) pathology and improve cognitive deficits [21], while MAO-A inhibitors acting synergistically with survivin suppressants, may inhibit prostate cancer cell growth, migration and invasion [22,23]. Based on the observation that hydrogen peroxide produced by MAO-A in the heart increases with age in rats, it has been suggested that MAO-A inhibitors may slow age-related impairment of cardiac function by reducing hydrogen peroxidemediated cardiac cellular degeneration [24].…”