Inhibition of autophagy enhances the anticancer activity of silver nanoparticles

• Published in: Autophagy Vol. 10; no. 11; pp. 2006 - 2020
• Main Authors: Lin, Jun, Huang, Zhihai, Wu, Hao, Zhou, Wei, Jin, Peipei, Wei, Pengfei, Zhang, Yunjiao, Zheng, Fang, Zhang, Jiqian, Xu, Jing, Hu, Yi, Wang, Yanhong, Li, Yajuan, Gu, Ning, Wen, Longping
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.11.2014
• Subjects: Androstadienes - chemistry; Animals; Antineoplastic Agents - chemistry; ANXA5, annexin A5; Apoptosis; Autophagy; autophagy inhibition; Basic Research Papers; CASP3, caspase 3, apoptosis-related cysteine peptidase; Cell Line, Tumor; Cell Survival; CTSB, cathepsin B; DLS, dynamic light scattering; DMEM, Dulbecco's Modified Eagle's medium; EGFP-LC3, enhanced green fluorescent protein-tagged LC3; Fibroblasts - metabolism; HeLa Cells; Humans; I-MEF, immortalized mouse embryonic fibroblast; ICP-MS, inductively coupled plasma-mass spectrometry; Ions; lysosomal function; Lysosomes - metabolism; Male; MDC, monodansylcadaverine; Melanoma, Experimental; Metal Nanoparticles - chemistry; Mice; Mice, Inbred C57BL; MTOR, mechanistic target of rapamycin; Neoplasms - metabolism; Neoplasms - pathology; P-MEF, primary mouse embryonic fibroblast; PI, propidium iodide; PI3K, phosphoinositide 3-kinase; PtdIns3K, phosphatidylinositol 3-kinase; PVP, polyvinylpyrrolidone; RNA, Small Interfering - metabolism; RPS6KB, ribosomal protein S6 kinase, 70 kDa; s.c., subcutaneously; Silver - chemistry; silver nanoparticles (Ag NPs); SQSTM1, sequestosome 1; TEM, transmission electron microscopy; tumor therapy; TUNEL, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling; UV-Vis, ultraviolet visible; XRD, X-ray diffraction; CASP3, caspase 3, apoptosis-related cysteine peptidase; PI3K, phosphoinositide 3-kinase; silver nanoparticles (Ag NPs); autophagy inhibition; s.c., subcutaneously; ANXA5, annexin A5; tumor therapy; RPS6KB, ribosomal protein S6 kinase, 70 kDa; XRD, X-ray diffraction; I-MEF, immortalized mouse embryonic fibroblast; PVP, polyvinylpyrrolidone; MTOR, mechanistic target of rapamycin; autophagy; PI, propidium iodide; EGFP-LC3, enhanced green fluorescent protein-tagged LC3; DMEM, Dulbecco's Modified Eagle's medium; TUNEL, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling; PtdIns3K, phosphatidylinositol 3-kinase; DLS, dynamic light scattering; TEM, transmission electron microscopy; CTSB, cathepsin B; lysosomal function; SQSTM1, sequestosome 1; ICP-MS, inductively coupled plasma-mass spectrometry; MDC, monodansylcadaverine; P-MEF, primary mouse embryonic fibroblast; UV-Vis, ultraviolet visible
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.36293

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.