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Abstract
The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules PI3K, PDK1, GSK3β, p70S6K, mTOR, and PTEN to analyze the PI3K/Akt/mTOR pathway. The results showed that Sal sensitization positively correlates with large reductions in p70S6K activation. Interestingly, Akt was the only signal protein to be significantly activated by Sal treatment. The Akt activation appeared to require the PI3K pathway as its activation was abolished by the PI3K inhibitors LY294002 and wortmannin. The Akt activation by Sal was conserved in the other cell lines analyzed, which originated from other organs. Both Akt activation and C-PARP production were proportionally increased with increased doses of Sal. In addition, the increased levels of pAkt were not reduced over the time course of the experiment. Co-treatment with Akt inhibitors sensitized the Sal-treated cancer cells. The results thereby suggest that Akt activation is increased in cells that survive Sal treatment and resist the cytotoxic effect of Sal. Taken together; these results indicate that Akt activation may promote the resistance of cancer cells to Sal.
Highlights
Salinomycin (Sal) was originally used to eliminate bacteria, fungi, and parasites [1,2,3]
We investigated the proteins altered by Sal in the Hs578T breast cancer cell line, which has been well-studied in previous studies [14,16,17,26]
We assessed the influence of Sal on the activation status and levels of Akt, Jnk, p38, Jak, Erk1/2, Jak1, Jak2, c-Src, PI3K, and IKKα/β, which are pivotal factors in the major signaling pathways regulating cell growth [18,19,20,21,22,23,24,25]
Summary
Salinomycin (Sal) was originally used to eliminate bacteria, fungi, and parasites [1,2,3] This drug has been exploited to inhibit the growth of tumor stem cells and chemoresistant cancer cells [4,5,6,7,8,9,10,11,12]. Sal sensitizes cancer cells to the effects of doxorubicin, etoposide, radiation, and anti-mitotic drugs, thereby inducing apoptosis as a result of DNA damage and reduced p21 protein levels due to increased proteasomal activity [14,16,17]. This novel finding regarding Sal-sensitization mechanisms could facilitate the therapeutic use of Sal in patients with cancer
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