PDE5A Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking through a Noncanonical cGMP-Dependent Pathway
Abstract
UNLABELLED: Noncanonical metabolic functions of signaling molecules contribute to cancer plasticity and metastatic progression. In this study, we demonstrated that phosphodiesterase type 5A (PDE5A) inhibitors, including sildenafil (Sild; Viagra), induced lysosomal cholesterol accumulation across multiple mouse and human cancer models, reducing cholesterol bioavailability and impairing cancer cell migration and metastasis. Cancer cells exhibited heightened sensitivity due to reduced lysosomal gene expression, rendering them particularly vulnerable to disrupted cholesterol trafficking. Mechanistically, elevated guanosine 3',5'-cyclic monophosphate (cGMP) bound the lysosomal cholesterol transporter NPC1, impairing cholesterol export and phenocopying Niemann-Pick type C pathology. The resulting cholesterol depletion disrupted membrane lipid rafts and mitochondrial bioenergetics, thereby limiting metastatic capacity and triggering compensatory sterol regulatory element-binding protein 2 (SREBP2) activation with increased cholesterol synthesis. Combining Sild with statins yields additive antimetastatic effects by concurrently blocking lysosomal cholesterol export and cholesterol biosynthesis. Consistently, analysis of digital health records demonstrated significantly improved survival among Sild users, with a dose-dependent additive benefit observed when combined with statins. Together, these findings identify increasing cGMP levels through PDE5A inhibition as a potential strategy…
Read the paper
Related studies
- 2024 update in heart failure
- Vascular involvement in idiopathic pulmonary fibrosis
- A novel technique- subendometrial autologous platelet rich plasma injection in patients with unresponsive thin endometrium undergoing frozen-thawed embryo transfer: a prospective cohort study
- Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial
- Combined Pulmonary Fibrosis and Emphysema (CPFE): A "New" Smoking-Related Interstitial Lung Disease (ILD)
- Impact of an acute 1-month cannabidiol treatment on pain and inflammation after a long bone fracture: a triple-blind randomised, placebo-controlled, clinical trial protocol
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.