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Cytotoxicity of [HuArgI (co)-PEG5000]-induced arginine deprivation to ovarian Cancer cells is autophagy dependent

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Summary

In this study, we assess arginine auxotrophy in ovarian cancer cells and attempt to target them using arginine deprivation induced by a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]. Ovarian cancer cells were sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation with IC50 values in the low pM range. Addition of excess L-citrulline rescued only one of three cell lines tested, indicating that the majority of cell lines are completely auxotrophic for arginine. The expression pattern of argininosuccinate synthetase (ASS1) confirmed the degree of auxotrophy of ovarian cancer cell lines with completely auxotrophic cells not expressing ASS1 and partially auxotrophic cells expressing the enzyme. Ovarian cancer cell lines were negative for annexinV staining while showing loss of membrane integrity and absence of caspase activation, indicating caspase-independent, non-apoptotic cell death. [HuArgI (Co)-PEG5000]-induced arginine deprivation led to extensive and prolonged activation of autophagy, which proved to be deleterious to cell survival since its inhibition led to a significant decrease in cytotoxicity. This indicates that the activation of autophagy following arginine-deprivation, rather than being protective, mediates cell cytotoxicity leading to death by autophagy.

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Funding

The work was supported by intramural funding from the Department of Natural Sciences of the Lebanese American University.

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Contributions

Nasreddine G, carried out the work, analyzed the data and wrote the manuscript. El-Sibai M, contributed to data analysis and provided critical feedback regarding the design of the study. Abi-Habib RJ, the principal investigator, designed the study, supervised the work, analyzed the data and contributed to writing the manuscript.

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Correspondence to Ralph J. Abi-Habib.

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Author Ghenwa Nasreddine declares that she has no conflict of interest. Author Mirvat EL-Sibai declares that she has no conflict of interest. Author Ralph J. Abi-Habib declares that he has no conflict of interest.

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Nasreddine, G., El-Sibai, M. & Abi-Habib, R.J. Cytotoxicity of [HuArgI (co)-PEG5000]-induced arginine deprivation to ovarian Cancer cells is autophagy dependent. Invest New Drugs 38, 10–19 (2020). https://doi.org/10.1007/s10637-019-00756-w

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