Enzymatic depletion of l‐Met using an engineered human enzyme as a novel therapeutic strategy for melanoma

Author:

Wilder Carly S.1,Chiou Jennifer2,Battenhouse Anna3,Saha Achinto1,Chen Zhao1,Kim Eunice1,Gadallah Mohamed I.24,Tiziani Stefano256,Georgiou George6789,Stone Everett67,DiGiovanni John156910ORCID

Affiliation:

1. Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin Austin Texas USA

2. Department of Nutritional Sciences The University of Texas at Austin Austin Texas USA

3. Center for Biomedical Research Support The University of Texas at Austin Austin Texas USA

4. Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy Assiut University Assiut Egypt

5. Department of Pediatrics, Dell Medical School The University of Texas at Austin Austin Texas USA

6. Department of Oncology, University of Texas Dell Medical School LiveSTRONG Cancer Institutes Austin Texas USA

7. Department of Molecular Biosciences The University of Texas at Austin Austin Texas USA

8. Department of Chemical Engineering The University of Texas at Austin Austin Texas USA

9. Institute of Cellular and Molecular Biology The University of Texas at Austin Austin Texas USA

10. Center for Molecular Carcinogenesis and Toxicology The University of Texas at Austin Austin Texas USA

Abstract

AbstractMany cancers, including melanoma, have a higher requirement for l‐methionine in comparison with noncancerous cells. In this study, we show that administration of an engineered human methionine‐γ‐lyase (hMGL) significantly reduced the survival of both human and mouse melanoma cells in vitro. A multiomics approach was utilized to identify global changes in gene expression and in metabolite levels with hMGL treatment in melanoma cells. There was considerable overlap in the perturbed pathways identified in the two data sets. Common pathways were flagged for further investigation to understand their mechanistic importance. In this regard, hMGL treatment induced S and G2 phase cell cycle arrest, decreased nucleotide levels, and increased DNA double‐strand breaks suggesting an important role for replication stress in the mechanism of hMGL effects on melanoma cells. Further, hMGL treatment resulted in increased cellular reactive oxygen species levels and increased apoptosis as well as uncharged transfer RNA pathway upregulation. Finally, treatment with hMGL significantly inhibited the growth of both mouse and human melanoma cells in orthotopic tumor models in vivo. Overall, the results of this study provide a strong rationale for further mechanistic evaluation and clinical development of hMGL for the treatment of melanoma skin cancer and other cancers.

Funder

Cancer Prevention and Research Institute of Texas

Publisher

Wiley

Subject

Cancer Research,Molecular Biology

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