Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Branching

Cancer Res. 2021 May 15;81(10):2625-2635. doi: 10.1158/0008-5472.CAN-20-2642. Epub 2021 Feb 18.

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. SIGNIFICANCE: These findings show that metastatic breast cancer cells depend on the fluvastatin-sensitive mevalonate pathway to support protein N-glycosylation, warranting immediate clinical testing of fluvastatin as an adjuvant therapy for breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Endoplasmic Reticulum / drug effects
  • Epithelial-Mesenchymal Transition
  • Female
  • Fluvastatin / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glycosylation
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mevalonic Acid / metabolism*
  • Mice
  • Mice, SCID
  • Prognosis
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Adjuvants, Immunologic
  • Fluvastatin
  • Mevalonic Acid

Grant support