Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo
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Qicheng Chen1,*, Li Ye1,*, Jiajun Fan1, Xuyao Zhang1, Huan Wang1, Siyang Liao1, Ping Song1, Ziyu Wang1, Shaofei Wang1, Yubin Li1,2, Jingyun Luan1, Yichen Wang1, Wei Chen1, Wenjing Zai3, Ping Yang4, Zhonglian Cao4 and Dianwen Ju1
1Department of Microbiological and Biochemical Pharmacy and Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, PR China
2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, PR China
4Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai, PR China
*These authors contributed equally to this work
Dianwen Ju, email: firstname.lastname@example.org
Keywords: autophagy, glioblastoma, asparaginase, apoptosis, reactive oxygen species
Received: December 21, 2016 Accepted: July 11, 2017 Published: July 20, 2017
Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model. Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment.
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