title: Involvement of autophagy in recombinant human arginase-induced cell apoptosis and growth inhibition of malignant melanoma cells.
abstract: Recombinant human arginase (rhArg) has been developed for arginine derivation therapy of cancer and is currently in clinical trials for a variety of malignant solid tumors. In this study, we reported for the first time that rhArg could induce obvious autophagy in human melanoma cells; inhibition of autophagy by chloroquine (CQ) significantly increased rhArg-induced cell apoptosis and growth inhibition of A375 cells. A significant increase in mitochondrial membrane potential loss and elevated intracellular reactive oxygen species (ROS) levels were detected in A375 cells after rhArg treatment when compared with control. Membrane transition inhibitor cyclosporine A blocked autophagy and accelerated cell death induced by rhArg, indicating that rhArg induced autophagy via mitochondria pathway. Furthermore, antioxidant N-acetyl-L-cysteine suppressed rhArg-induced autophagy and rescued cells from cell growth inhibition, suggesting that ROS played an important role in rhArg-induced A375 cell growth inhibition and autophagy. Akt/mTOR signaling pathway was involved in autophagy induced by rhArg in a time-dependent manner. Moreover, rhArg could induce ERK1/2 activation in a dose- and time-dependent manner and rhArg-induced autophagy was attenuated when p-ERK1/2 was inhibited by MEK 1/2 inhibitor, U0126. Taken together, this study provides new insight into the molecular mechanism of autophagy involved in rhArg-induced cell apoptosis and growth inhibition, which facilitates the development of rhArg in combination with CQ as a potential therapy for malignant melanoma.
authors.affiliation: Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Xunlong
authors.initials: X
authors.lastname: Shi
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.forename: Zongshu
authors.initials: Z
authors.lastname: Xian
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhang
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.forename: Haifeng
authors.initials: H
authors.lastname: Hu
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008544:Melanocytes / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D001119:Arginase