Role of Survivin as a Resistor against Nanotoxicity in Cancer Cells -Autophagy as a Key Mechanism-
Loading...
Date issued
Authors
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Reuse License
Abstract
The smallest member of the inhibitor of apoptosis protein family Survivin utilized as biomarker for malignant tumor progression, treatment resistance, and associated with impacted apoptosis and cellular processes like autophagy. Nanotechnology emerges as a promising tool to target Survivin-related pathways in overcoming tumor resistance. Pristine silica nanoparticles (SiNP) were utilized to investigate their influence on Survivin-expressing cancer cells. Thereby, the SiNP toxicity was concentration and time-dependent, which depended on a serum-free environment, leading to apoptotic and necrotic phenotypes with increased autophagic characteristics. Mechanistically, SiNP generated ROS mainly through mitochondrial stress increase, activated stress kinase p38, and downregulated pro-survival kinases Akt and MAPK 44/42. However, SiNP destabilized the cytoskeleton, triggering autophagy through a PI3K/Akt/mTOR-independent pathway, and surprisingly, impaired autophagy in the late stage, resulting in the accumulation of autophagy-related organelles and cell death. Survivin overexpression delayed the cell death by suppressing autophagy and stabilizing the cytoskeleton. In addition, Survivin altered the mitochondrial phenotype, suppressed p38 activation in response to SiNP-generated ROS stress, in turn p38 inhibition increased the cell viability of Survivin-overexpressing cells. Overall, the study supports the hypothesis that autophagy plays a crucial role in Survivin-induced resistance, emphasizing its consideration as a target in novel cancer therapies addressing Survivin.