Abstract
Several literature has shown that salinomycin (Sal) is able to kill various types of cancer cells through different signaling pathways. However, its effect on melanoma has seldom been reported. We examined the anti-cancer efficacy of Sal in melanoma cell lines, and found six of eight cell lines were sensitive to Sal. Given the fact that the roles of Sal are diverse in different cancer types, we were eager to figure out the mechanism involved in the current study. We noticed the most sensitive line, SK-Mel-19, showed a typical morphological change after Sal treatment. The autophagy inhibitor, 3-MA, could effectively suppress Sal-induced cell death. It could also facilitate the increase of autophagic markers and reduce the turnover of autophagosomes, which resulted in an aberrant autophagic flux. On the other hand, Sal could stimulate endoplasmic reticulum stress and cause an accumulation of dysfunctional mitochondria. We also discovered a potential correlation between LC3B mRNA level and its sensitivity to Sal in 43 clinical melanoma samples. Overall, our results indicated that Sal could have multiple effect on melanoma cells and induce autophagic cell death in certain kinds of cells, which provided a new insight into the chemotherapy for melanoma.
Highlights
Several literature has shown that salinomycin (Sal) is able to kill various types of cancer cells through different signaling pathways
We found that LC3B-II significantly increased upon Sal treatment in a time dependent manner, which indicated the accumulation of lipidation of LC3B-I and formation of LC3B-II (Fig. 3a), while the protein level of Beclin-1, another protein relevant to autophagy[30], remained unchanged (Fig. 3b)
When we examined the expression of autophagy-related genes in melanoma lines, we occasionally found that LC3B mRNA was especially highly expressed in the Sal-sensitive lines (M21 and SK-Mel-19, Fig. 7a)
Summary
Several literature has shown that salinomycin (Sal) is able to kill various types of cancer cells through different signaling pathways. The autophagy inhibitor, 3-MA, could effectively suppress Sal-induced cell death. It could facilitate the increase of autophagic markers and reduce the turnover of autophagosomes, which resulted in an aberrant autophagic flux. Most studies support that Sal triggers cell apoptosis, an essential mechanism by which anticancer drugs damage tumor cells[12,13,14], while others have proposed necrosis and autophagic cell d eath[15,16,17]. Macroautophagy (autophagy) has recently emerged as an essential regulator of cell death pathways involved in cancer initiation, development, and p rogression[18,19,20,21]. Autophagic cell death is primarily a morphologic definition (i.e. cell death associated with autophagosomes/autolysosomes), and there is still no conclusive evidence that a specific mechanism of autophagic death e xists[28]
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