Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity.

Abstract

Extensive studies in prostate cancer and other malignancies have revealed that l-methionine (l-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum l-Met, either via partial dietary restriction or with bacterial l-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial l-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode l-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of l-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum l-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis.

• Authors: Wei-Cheng Lu, Achinto Saha, Wupeng Yan, Kendra Garrison, Candice Lamb, Renu Pandey, Seema Irani, Alessia Lodi, Xiyuan Lu, Stefano Tiziani, Yan Jessie Zhang, George Georgiou, John DiGiovanni, Everett Stone
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 23 Pg. 13000-13011 (06 09 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32434918 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• Reactive Oxygen Species
• Recombinant Proteins
• Methionine
• Poly(ADP-ribose) Polymerases
• Cystathionine gamma-Lyase

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cystathionine gamma-Lyase (genetics, isolation & purification, pharmacology, therapeutic use)
• DNA Damage (drug effects)
• Enzyme Assays
• Humans
• Male
• Methionine (antagonists & inhibitors, blood, metabolism)
• Mice
• Mutagenesis, Site-Directed
• Poly(ADP-ribose) Polymerases (metabolism)
• Prostatic Neoplasms (blood, drug therapy)
• Reactive Oxygen Species (metabolism)
• Recombinant Proteins (genetics, isolation & purification, pharmacology, therapeutic use)
• Toxicity Tests, Acute
• Xenograft Model Antitumor Assays