title: Inhibition of autophagy enhances the anticancer activity of silver nanoparticles.
abstract: Silver nanoparticles (Ag NPs) are cytotoxic to cancer cells and possess excellent potential as an antitumor agent. A variety of nanoparticles have been shown to induce autophagy, a critical cellular degradation process, and the elevated autophagy in most of these situations promotes cell death. Whether Ag NPs can induce autophagy and how it might affect the anticancer activity of Ag NPs has not been reported. Here we show that Ag NPs induced autophagy in cancer cells by activating the PtdIns3K signaling pathway. The autophagy induced by Ag NPs was characterized by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. Consistent with these properties, the autophagy induced by Ag NPs promoted cell survival, as inhibition of autophagy by either chemical inhibitors or ATG5 siRNA enhanced Ag NPs-elicited cancer cell killing. We further demonstrated that wortmannin, a widely used inhibitor of autophagy, significantly enhanced the antitumor effect of Ag NPs in the B16 mouse melanoma cell model. Our results revealed a novel biological activity of Ag NPs in inducing cytoprotective autophagy, and inhibition of autophagy may be a useful strategy for improving the efficacy of Ag NPs in anticancer therapy.
authors.affiliation: a Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences ; University of Science and Technology of China ; Hefei , China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Peipei
authors.initials: P
authors.lastname: Jin
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wei
authors.forename: Yunjiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Jiqian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.forename: Longping
authors.initials: L
authors.lastname: Wen
mesh_terms: D000730:Androstadienes / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D002470:Cell Survival; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007477:Ions; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D012834:Silver / Q000737:chemistry*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D007477:Ions; D034741:RNA, Small Interfering; D012834:Silver; D000077191:Wortmannin
keywords: ANXA5, annexin A5; CASP3, caspase 3, apoptosis-related cysteine peptidase; CTSB, cathepsin B; DLS, dynamic light scattering; DMEM, Dulbecco's Modified Eagle's medium; EGFP-LC3, enhanced green fluorescent protein-tagged LC3; I-MEF, immortalized mouse embryonic fibroblast; ICP-MS, inductively coupled plasma-mass spectrometry; MDC, monodansylcadaverine; MTOR, mechanistic target of rapamycin; P-MEF, primary mouse embryonic fibroblast; PI, propidium iodide; PI3K, phosphoinositide 3-kinase; PVP, polyvinylpyrrolidone; PtdIns3K, phosphatidylinositol 3-kinase; RPS6KB, ribosomal protein S6 kinase, 70 kDa; SQSTM1, sequestosome 1; TEM, transmission electron microscopy; TUNEL, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling; UV-Vis, ultraviolet visible; XRD, X-ray diffraction; autophagy; autophagy inhibition; lysosomal function; s.c., subcutaneously; silver nanoparticles (Ag NPs); tumor therapy