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PDE5A Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking through a

Yarden Ariav1, Samah Hayek2,3, Thomas Cantore4

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Cancer Research
|July 14, 2026
PubMed

Insights

Phosphodiesterase type 5 A (PDE5a) inhibitors like sildenafil cause cancer cells to accumulate cholesterol, hindering metastasis. Combining sildenafil with statins enhances survival by blocking cholesterol export and synthesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-canonical metabolic functions of signaling molecules are key drivers of cancer plasticity and metastasis.
  • Cholesterol metabolism plays a critical role in cancer progression and cell migration.

Purpose of the Study:

  • To investigate the antimetastatic effects of phosphodiesterase type 5 A (PDE5a) inhibitors.
  • To elucidate the molecular mechanisms by which PDE5a inhibitors impact cancer cell cholesterol metabolism and metastasis.

Main Methods:

  • Utilized multiple mouse and human cancer models to assess PDE5a inhibitor effects.
  • Investigated the interaction between cyclic guanosine monophosphate (cGMP) and the lysosomal cholesterol transporter NPC1.
  • Analyzed digital health records to evaluate patient survival data.

Main Results:

  • Sildenafil (Viagra) induced lysosomal cholesterol accumulation in cancer cells, reducing cholesterol bioavailability and impairing migration.
  • Elevated cGMP levels bound NPC1, disrupting cholesterol export and mimicking Niemann-Pick type C pathology.
  • Combined sildenafil and statin therapy showed additive antimetastatic effects and improved patient survival.

Conclusions:

  • PDE5a inhibition represents a potential strategy to restrict cancer metastasis by disrupting cholesterol trafficking.
  • The findings provide a mechanistic basis for the observed survival benefits of sildenafil, particularly when combined with statins.
  • Targeting lysosomal cholesterol homeostasis offers a novel therapeutic approach for cancer treatment.

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