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Blocking autophagy enhanced leukemia cell death induced by recombinant human arginase

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Tumor Biology

Abstract

Recombinant human arginase (rhArg) is an arginine-degrading enzyme that has been evaluated as effective therapeutics for varieties of malignant tumors and is in clinical trials for hepatocellular carcinoma (HCC) treatment nowadays. Our previous studies have reported that rhArg could induce autophagy and apoptosis in lymphoma cells and inhibiting autophagy could enhance the efficacy of rhArg on lymphoma. However, whether rhArg could induce autophagy and what roles autophagy plays in leukemia cells are unclear. In this study, we demonstrated that rhArg treatment could lead to the formation of autophagosomes and the upregulation of microtubule-associated protein light chain 3 II (LC3-II) in human promyelocytic leukemia HL-60 cells and human acute T cell leukemia Jurkat cells. Furthermore, inhibiting autophagy using 3-methyladenine (3-MA) or chloroquine (CQ) could significantly enhance rhArg-induced cell growth inhibition and apoptosis. Taken together, these findings indicated that rhArg induced autophagy in leukemia cells and inhibiting autophagy enhanced anti-leukemia effect of rhArg, which might encourage the treatment of leukemia by targeting arginine depletion and autophagy in clinics.

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Acknowledgments

This work was supported by grants from the National Key Basic Research Program of China (2013CB932502, 2015CB931800), the National Natural Science Foundation of China (81573332), and Shanghai Science and Technology Funds (14431900200).

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    Authors and Affiliations

    1. Department of Biosynthesis and The Key Laboratory of Smart Drug Delivery, MOE, School of Pharmacy, Fudan University, Shanghai, 201203, China

      Yubin Li, Xian Zeng, Shaofei Wang, Jiajun Fan, Ziyu Wang, Ping Song & Dianwen Ju

    2. Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

      Xiaobin Mei

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    Yubin Li and Xian Zeng contributed equally to this work.

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    Supplementary Figure 1

    rhArg induced formation of autophagosomes in leukemia cells. HL-60 and Jurkat cells were treated with or without 1 IU/ml of rhArg for 24 h. Cell samples were prepared for transmission electron microscopy analysis as described in “Materials and methods.” Autophagosomes were counted, and the data were presented as the means ± SD of four samples. **p < 0.01 versus Ctrl; ***p < 0.001 versus Ctrl (JPEG 19 kb)

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    Li, Y., Zeng, X., Wang, S. et al. Blocking autophagy enhanced leukemia cell death induced by recombinant human arginase. Tumor Biol. 37, 6627–6635 (2016). https://doi.org/10.1007/s13277-015-4253-x

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