Abstract
Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.
Highlights
Cutaneous melanoma is a type of malignant disease with relatively low but worldwide increasing incidence
Prepared cultures along with cells of stabilized melanoma line Bowes and primary melanocytes HEM were used for the initial screening of their proliferation rates, total as well as free zinc content and metallothionein IIA expression
Since melanoma cells harbored varied free zinc content, we focused on biological effects of further zinc loading in those cultures with previously determined low free zinc content (M5 cells), average free zinc content (M10 cells), and high free zinc content (M9 cells)
Summary
Cutaneous melanoma is a type of malignant disease with relatively low but worldwide increasing incidence. While treatable in early stages by surgical resection, advanced forms of this condition show increased propensity for biological aggressiveness, systemic spread, and chemoresistance, resulting in treatment failure and high mortality rates among patients Melanoma cells in these stages present with a heterogeneous genetic background characterized by a high prevalence of somatic mutations and the functional plasticity, favoring an aggressive and invasive phenotype associated with developed chemoresistance [1]. The presence of a higher autophagic flux in metastatic melanoma cells as compared to primary melanoma and melanocytes is regarded as one of the key transitions towards aggressive melanoma phenotype [14] Such a conclusion based on in vitro experiments is further supported by findings of higher expression of autophagic LC3B and Beclin-1 proteins in samples of patients with advanced/metastatic melanoma as compared to non-invasive, primary tumors [15,16,17].
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