Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2

Abstract

Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APCCdh1–Skp2–p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance.

Geno- and cytotoxicity of salinomycin in human nasal mucosa and peripheral blood lymphocytes

“…Caspase-independent apoptosis was postulated by Fuchs and colleagues who demonstrated that salinomycin activates a distinct apoptotic pathway, which was not accompanied by cell cycle arrest and that was independent from the tumor suppressor protein p53, caspase activation, and the CD95/CD95L system (Fuchs et al, 2009). There is also a report on cell death induction via inactivation of Stat 3 (Koo et al, 2013).…”

Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity

“…Both have been shown to induce cell death via apoptotic and autophagic pathways (57-59). Moreover, the HDAC inhibitors have also been shown to induce dedifferentiation, and in so doing reduce tumor growth and metastasis (60).…”

The Role of FBXL Subfamily of F-box Proteins in Tumorigenesis

“…Moreover, inhibition of cell proliferation by blocking the G1 to S transition was also observed, as was downregulation of the levels of phosphorylated Cyclin E (Thr62) and p27Kip1 (Thr187). Furthermore, another small molecule, Salinomycin, inhibited STAT3 activity and thus decreased expression of Stat3-target genes including Skp2 [ 78 ]. Salinomycin was found to induce degradation of Skp2, accompanied by p27 accumulation, cell cycle arrest, and apoptosis.…”