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acidic vescicular organelles, the down regulation of AKT, p-AKT, HSP90 and p62 the increment of ATG5, ATG7 and beclin-1 and the conversion of LC3-I to LC3-II. Concerning the apoptosis, only the 11% of treated cells underwent to apoptotic cell death and accordingly, no DNA fragmentation was evident in our analysis at 24h, although the increment of Ag+-DNA binding was evident after 48h of treatment. Several evidences suggested that activation of autophagy, is also dependent by the accumulation of oxidatively damaged proteins and subsequent endoplasmic reticulum stress, or mitochondrial damage [34, 64–66]. Our proteomic results are in agreement with these observations. The differentially proteins identified so far, highlights important pathways involved in the mechanism of action of AgNPs-EPSaer. The endoplasmic reticulum (ER) is a well-orchestrated protein-folding machine composed of protein chaperones, proteins that catalyze protein folding, and sensors that detect the presence of misfolded or unfolded proteins. The protein folding and generation of reactive oxygen species (ROS) as a byproduct of protein oxidation in the ER are closely linked events, and persistent oxidative stress and protein misfolding initiate cell death. Autophagy is emerging as an important mediator of pathological responses and engages in cross-talk with ROS. Oxidative stress is inseparably linked to mitochondrial dysfunction, as mitochondria are both generators of and targets for reactive species. Moreover, the mitochondrial turnover is dependent on autophagy. We believe that proteomic pathways disclosed in this study represent an important advance about the mechanisms of AgNPs-EPSaer induced toxicity according to a modern omic-research direction in cancer therapy. Figure 11: Excitation-emission spectroscopy of DNA. Determination of intrinsic DNA fluorescence. The DNA was extracted from SKBR3 treated and untreated with AgNPs-EPsaer. The Eex was set at 270 nm and the Eem were ranging from 200 to 700 nm. The relative fluorescence units (RFU) of intensities and the 3 emission peaks (1a, 1b and 2) were reported. R1 and R2 corresponded to the Rayleigh scattering peaks. www.impactjournals.com/oncotarget 9697 OncotargetPDF Image | Anticancer activity of biogenerated silver nanoparticles
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