Activation of autophagy following [HuArgI (Co)-PEG5000]-induced arginine deprivation mediates cell death in colon cancer
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RESEARCH ARTICLE
Activation of autophagy following [HuArgI (Co)‑PEG5000]‑induced arginine deprivation mediates cell death in colon cancer cells Mirna Swayden2 · Amira Bekdash1 · Isabelle Fakhoury1 · Oula El‑Atat1 · Jamila Borjac‑Natour2 · Mirvat El‑Sibai1 · Ralph J. Abi‑Habib1 Received: 9 May 2020 / Accepted: 17 September 2020 © Japan Human Cell Society 2020
Abstract Deregulating cellular energetics by reprogramming metabolic pathways, including arginine metabolism, is critical for cancer cell onset and survival. Drugs that target the specific metabolic requirements of cancer cells have emerged as promising targeted cancer therapeutics. In this study, we investigate the therapeutic potential of targeting colon cancer cells using arginine deprivation induced by a pegylated cobalt-substituted recombinant human Arginase I [HuArgI (Co)-PEG5000]. Four colon cancer cell lines were tested for their sensitivity to [HuArgI (Co)-PEG5000] as well as for their mechanism of cell death following arginine deprivation. All four cell lines were sensitive to arginine deprivation induced by [HuArgI (Co)-PEG5000]. All cells expressed ASS1 and were rescued from arginine deprivation-induced cytotoxicity by the addition of excess l-citrulline, indicating they are partially auxotrophic for arginine. Mechanistically, cells treated with [HuArgI (Co)-PEG5000] were negative for AnnexinV and lacked caspase activation. Further investigation revealed that arginine deprivation leads to a marked and prolonged activation of autophagy in both Caco-2 and T84 cell lines. Finally, we show that [HuArgI (Co)-PEG5000] causes cell death by sustained activation of autophagy as evidenced by the decrease in cell cytotoxicity upon treatment with chloroquine, an autophagy inhibitor. Altogether, these data demonstrate that colon cancer cells are partially auxotrophic for arginine and sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation. They also show that the activation of autophagy does not play protective roles but rather, induces cytotoxicity and leads to cell death. Keywords [HuArgI (co)-PEG5000] · Colorectal cancer · Arginine auxotrophy · Autophagy
Introduction Colorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of cancer-related mortality worldwide [1]. CRC death rate has been declining due to better screening and improved treatment, however, prognosis of patients with stage IV disease remains poor with an overall 5-year survival rate ranging from 7.4 to 14.2%, Mirna Swayden and Amira Bekdash both authors contributed equally to this work. * Ralph J. Abi‑Habib [email protected] 1
Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut 1102 2801, Lebanon
Department of Biological and Environmental Sciences, School of Arts and Sciences, Beirut Arab University, Beirut, Lebanon
2
depending on the age group [1, 2]. Hence, the need for a better understanding of CRC and for more potent and selective therapeutic approaches for the treatment of late s
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