Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity.
Wei-Cheng LuAchinto SahaWupeng YanKendra GarrisonCandice LambRenu PandeySeema IraniAlessia LodiXiyuan LuStefano TizianiYan Jessie ZhangGeorge GeorgiouJohn DiGiovanniEverett M StonePublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- prostate cancer
- tyrosine kinase
- cell death
- dna damage
- endothelial cells
- oxidative stress
- radical prostatectomy
- weight loss
- induced pluripotent stem cells
- reactive oxygen species
- endoplasmic reticulum stress
- dna repair
- type diabetes
- bariatric surgery
- signaling pathway
- mental health
- stem cells
- cell therapy
- mesenchymal stem cells
- cell proliferation
- bone marrow
- insulin resistance
- single cell
- pi k akt
- glycemic control