Enhancement of anti-tumor activity in melanoma using arginine deiminase fused with 30Kc19 alpha protein
- Authors
- Lee, Haein; Park, Geunhwa; Kim, Seulha; Son, Boram; Joo, Jinmyoung; Park, Hee Ho; Park, Tai Hyun
- Issue Date
- Nov-2022
- Publisher
- SPRINGER
- Keywords
- Arginine deiminase (ADI); Melanoma; Solubility enhancer; Enzyme stabilizer; Cell-penetrating protein
- Citation
- APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, v.106, no.22, pp.7531 - 7545
- Indexed
- SCIE
SCOPUS
- Journal Title
- APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
- Volume
- 106
- Number
- 22
- Start Page
- 7531
- End Page
- 7545
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/185800
- DOI
- 10.1007/s00253-022-12218-0
- ISSN
- 0175-7598
- Abstract
- Arginine deiminase (ADI) is a microbial-derived enzyme which catalyzes the conversion of l-arginine into l-citrulline. ADI originating from Mycoplasma has been reported to present anti-tumor activity against arginine-auxotrophic tumors, including melanoma. Melanoma cells are sensitive to arginine depletion due to reduced expression of argininosuccinate synthase 1 (ASS1), a key enzyme for arginine biosynthesis. However, clinical applications of recombinant ADI for melanoma treatment present some limitations. Since recombinant ADI is not human-derived, it shows instability, proteolytic degradation, and antigenicity in human serum. In addition, there is a problem of drug resistance issue due to the intracellular expression of once-silenced ASS1. Moreover, recombinant ADI proteins are mainly expressed as inclusion body forms in Escherichia coli and require a time-consuming refolding process to turn them back into active form. Herein, we propose fusion of recombinant ADI from Mycoplasma hominis and 30Kc19 alpha, a cell-penetrating protein which also increases stability and soluble expression of cargo proteins, to overcome these problems. We inserted matrix metalloproteinase-2 cleavable linker between ADI and 30Kc19 alpha to increase enzyme activity in melanoma cells. Compared to ADI, ADI-LK-30Kc19 alpha showed enhanced solubility, stability, and cell penetration. The fusion protein demonstrated selective cytotoxicity and reduced drug resistance in melanoma cells, thus would be a promising strategy for the improved efficacy in melanoma treatment.
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