[HuArgI (co)-PEG5000]-induced arginine deprivation leads to autophagy dependent cell death in pancreatic cancer cells
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PRECLINICAL STUDIES
[HuArgI (co)-PEG5000]-induced arginine deprivation leads to autophagy dependent cell death in pancreatic cancer cells Nathalie Khalil 1 & Ralph J. Abi-Habib 1 Received: 11 October 2019 / Accepted: 21 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Summary In this study, we examined the sensitivity of pancreatic cancer cells to [HuArgI (Co)-PEG5000]-induced arginine deprivation as well as the mechanisms underlying deprivation-induced cell death. [HuArgI (Co)-PEG5000]-induced arginine deprivation was cytotoxic to all cell lines tested with IC50 values in the pM range at 72 h post-treatment. Three of the five cell lines were rescued by the addition of excess L-citrulline and expressed ASS1, indicating partial arginine auxotrophy. The remaining two cell lines, on the other hand, were not rescued by the addition of L-citrulline and did not express ASS1, indicating complete auxotrophy to arginine. In addition, all cell lines exhibited G0/G1 cell cycle arrest, in the surviving cell fraction, at 72 h following arginine deprivation. Analysis of the type of cell death revealed negative staining for annexin V and a lack of caspase activation in all five cancer cell lines, following treatment, indicating that arginine deprivation leads to caspase-independent, non-apoptotic cell death. Finally, we demonstrated that arginine deprivation leads to a marked activation of autophagy and that inhibition of this autophagy greatly decreases cytotoxicity, indicating that arginine deprivation induces autophagic cell death in pancreatic cancer cells. We have shown that pancreatic cancer cells are auxotrophic for arginine and sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation, hence demonstrating that arginine deprivation is a potentially potent and selective treatment for pancreatic cancer. We have also demonstrated that autophagy is activated following arginine-deprivation and that its prolonged activation leads to autophagic cell death. Keywords Pancreatic cancer . [HuArgI (Co)-PEG5000] . Arginine deprivation . Autophagy . Autophagic cell death
Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid malignancies with a poor prognosis and a five-year overall survival rate of 6 to 7% [1, 2]. Surgical resection presents the only viable treatment approach for PDAC given the absence of efficient therapeutics. However, in most cases PDAC displays, at diagnosis, local invasion and/ or metastasis rendering it unresectable [2–4]. Therefore, there’s an urgent need to develop novel, effective and selective strategies for targeting pancreatic cancer. One such strategy consists of targeting arginine auxotrophy in pancreatic cancer cells using arginine deprivation induced by a pegylated,
* Ralph J. Abi-Habib [email protected] 1
Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, Lebanon
cobalt-substituted, human recombinant Arginase I [HuArgI (Co)-PEG5000]. In normal cells,
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