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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-06, Vol.117 (23), p.13000-13011
• Main Authors: Lu, Wei-Cheng, Saha, Achinto, Yan, Wupeng, Garrison, Kendra, Lamb, Candice, Pandey, Renu, Irani, Seema, Lodi, Alessia, Lu, Xiyuan, Tiziani, Stefano, Zhang, Yan Jessie, Georgiou, George, DiGiovanni, John, Stone, Everett
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Allografts; Animals; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; BASIC BIOLOGICAL SCIENCES; Biodegradation; Biological Sciences; Cell death; Cell Line, Tumor; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - isolation & purification; Cystathionine gamma-Lyase - pharmacology; Cystathionine gamma-Lyase - therapeutic use; Degradation; Deoxyribonucleic acid; Depletion; Diet; Dietary restrictions; DNA; DNA damage; DNA Damage - drug effects; Enzyme Assays; Enzymes; Genomes; hMGL; Humans; Immunogenicity; L-methionine depletion; Male; Metabolites; Methionine; Methionine - antagonists & inhibitors; Methionine - blood; Methionine - metabolism; Mice; Mutagenesis, Site-Directed; Phagocytosis; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Prostate cancer; Prostatic Neoplasms - blood; Prostatic Neoplasms - drug therapy; Reactive oxygen species; Reactive Oxygen Species - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Ribose; Toxicity; Toxicity Tests, Acute; Tumorigenesis; Weight loss; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1917362117

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.