期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：23
页码：13000-13011
DOI：10.1073/pnas.1917362117
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：prostate cancer ; l -methionine depletion ; hMGL
