Silver Nanoparticles Induced Autophagy In Tumor Therapy And Implied Mechanism

As the most wildly be used nano materials, silver nanoparticles (Ag NPs) show a fine application prospect in photology, electricity, mechanics, magnetics, catalysis, biology. Ag NPs also exhibit a variety of biological effects, such as antibacterial, antifungal, antiviral and anti-inflammatory, and thus are attracting interest for a wide range of biomedical applications. Numerous reports have documented the remarkable ability of Ag NPs to elicit cytotoxicity in cancer cells, such as oxidative stress, DNA damage, apoptosis and necrosis in cancer cells. A variety of nanoparticles, such as up-conversion luminescent nanomaterial, C60, gold nanoparticles, quantum dot, have been shown to induce autophagy, a critical cellular degradation process to maintain normal metabolism in organisms, and the elevated autophagy in most of these situations promote cell death. Whether Ag NPs can induce autophagy and how it might affect the cell fate have 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, suggesting that Ag NPs induced complete autophagy in treated cells.Ag NPs are cytotoxic to cancer cells and have been shown a good therapeutic effect to Dalton’s lymphoma ascites tumor and Malignant melanoma. Moreover, the antiangiogenic property of Ag NPs also makes it possess excellent potential as an anti-tumor agent. So we explored how the autophagy might affect the anti-cancer activity of Ag NPs. We found the autophagy induced by Ag NPs promoted cell survival, as inhibition of autophagy by either chemical inhibitors (wortmannin or bafilomycin A1) or ATG5siRNA enhanced Ag NPs-elicited cancer cell killing. This put Ag NPs in the minority group of inorganic nanoparticles while the predominant majority of inorganic nanoparticles with autophagy-inducing ability elicit death-promoting autophagy. It also suggested that we can use the autophagy inhibitiors to enhance the antitumor efficacy of Ag NPs. We further demonstrated that wortmannin, a widely-used inhibitor of autophagy, significantly enhanced the anti-tumor effect of Ag NPs in the B16melanoma animal model.Ag NPs induced protective autophagy in cells, so we explored the further mechanism of protective autophagy induced by Ag NPs treatment. Then we found transcription factor EB (TFEB), an master regulator of autophagy and lysosomal biogenesis, translocated to the nucleus by Ag NPs treatment. But the mechanism of TFEB translocation to the nucleus is different from the mechanism that has been reported. So we were trying to find a new signaling pathway to explain the phenomenon that we found in Ag NPs treated cell. In addition, AuCu nanoparticle and QDs caused TFEB translocation to the nucleus, It is coincidence that QDs and CuO nanoparticles have been reported to induce protective autophagy. So we speculate that TFEB translocation to the nucleus play an important role in nanoparticles induced protective autophagy.Our results revealed a novel biological activity of Ag NPs in inducing cyto-protective autophagy, and inhibition of autophagy may be a useful strategy for improving the efficacy of Ag NPs in anti-cancer therapy. Moreover, our research will help us understand more about the mechanism of the protective autophagy.