Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Branching
Abstract
Aberrant N-glycan Golgi remodeling and metabolism are associated with epithelial–mesenchymal transition (EMT) and metastasis in patients with breast cancer. Despite this association, the N-glycosylation pathway has not been successfully targeted in cancer. Here, we show that inhibition of the mevalonate pathway with fluvastatin, a clinically approved drug, reduces both N-glycosylation and N-glycan-branching, essential components of the EMT program and tumor metastasis. This indicates novel cross-talk between N-glycosylation at the endoplasmic reticulum (ER) and N-glycan remodeling at the Golgi. Consistent with this cooperative model between the two spatially separated levels of protein N-glycosylation, fluvastatin-induced tumor cell death was enhanced by loss of Golgi-associated N-acetylglucosaminyltransferases MGAT1 or MGAT5. In a mouse model of postsurgical metastatic breast cancer, adjuvant fluvastatin treatment reduced metastatic burden and improved overall survival. Collectively, these data support the immediate repurposing of fluvastatin as an adjuvant therapeutic to combat metastatic recurrence in breast cancer by targeting protein N-glycosylation at both the ER and Golgi.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 18, 2021
- Source ID
- 10.1158/0008-5472.can-20-2642
Entities
People
- Cunjie Zhang
- David Cescon
- Emily Branchard
- James W Dennis
- Jenna E van Leeuwen
- Joseph Longo
- Linda Z Penn
- Mohamad Elbaz
- Richard R. Drake
- Rosemary Yu
Organizations
- Medical University of South Carolina
- Mount Sinai Hospital, Toronto
- The Breast Cancer Research Foundation
- University of Toronto