S-nitrosoglutathione Inhibits the Growth of Androgen-Receptor Dependent and Castration Resistant Prostate Cancer by Modulating FOXM1 Signaling
Year: 2022
Type: preprint
Abstract: Castration resistant prostate cancer (CRPC) is an advanced form of prostate cancer associated with loss of androgen receptor activity and resistance to AR-targeted therapies. CRPC is often associated with higher metastasis, invasion, and proliferation. Thus, there’s a strong need for additional molecular markers in CRPC, and therapies that target them directly. Transcriptomic profiling of prostate cancer patients revealed an upregulated signature specific to high-grade tumors in cell cycle progression, E2F targets, G2M checkpoint, DNA repair, Aurora Kinase B, and FOXM1 pathway. Validation in a separate cohort of neuroendocrine prostate cancer patients, the most resistant and invasive form of CRPC which lacks AR expression, showed CCP signature as a dominant driver gene set for NEPC. Moreover, high expression of mRNA targets in each of these pathways is associated with poor overall survival in NEPC patients. Gene set variation analysis revealed a strong inverse correlation between AR signaling and CCP.31, set of 31 markers associated with high proliferation, and a positive correlation between CCP.31 and NEPC signature. FOXM1, a prioritized candidate in CCP is shown to be upregulated in CRPC cell lines and human clinical sections of Gleason 9 patients. GSNO, a nitric oxide donor, known for its inhibitory effect on cell proliferation and an effective inhibitor of cell cycle checkpoints, was able to reverse CCP signature both in-vitro and in-vivo. GSNO exhibits a dependence on AR signaling in-vitro by showing mild effect on CRPC clones, but successfully inhibits tumor growth of AR-null CRPC xenografts. FOXM1 is also targeted by GSNO in-vivo and in-vitro models of both CRPC and AD prostate cancer. This establishes an important link between androgen receptor status in prostate cancer and proposes nitric oxide donors as therapeutic intervention. GSNO is effective against AR-null castration resistant prostate cancer. Significance Nitric oxide donor, S-glutathione-transferase inhibits tumor growth of castration resistant prostate cancer, regardless of androgen receptor expression status by targeting FOXM1, a critical regulator of cell cycle progression.
Institution: University of Miami
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mesenchymal stem cell therapy for endothelial dysfunction in diabetes, Nitric Oxide and sex differences in cardiac repair, Cell Based Therapy for Non-Ischemic Dilated Cardiomyopathy, Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis, Cardioprotective Effect of Growth Hormone Releasing Hormone
OpenAlex ID: W4292553556