Abstract
BackgroundSTAT3 [1] has been shown to be dysregulated in nearly every major cancer, including osteosarcoma (OS). Constitutive activation of STAT3, via aberrant phosphorylation, leads to proliferation, cell survival and resistance to apoptosis. The present study sought to characterize the biologic activity of a novel allosteric STAT3 inhibitor, LLL12, in canine OS cell lines.ResultsWe evaluated the effects of LLL12 treatment on 4 canine OS cell lines and found that LLL12 inhibited proliferation, induced apoptosis, reduced STAT3 phosphorylation, and decreased the expression of several transcriptional targets of STAT3 in these cells. Lastly, LLL12 exhibited synergistic anti-proliferative activity with the chemotherapeutic doxorubicin in the OS lines.ConclusionLLL12 exhibits biologic activity against canine OS cell lines through inhibition of STAT3 related cellular functions supporting its potential use as a novel therapy for OS.
Highlights
STAT3 [1] has been shown to be dysregulated in nearly every major cancer, including osteosarcoma (OS)
The importance of STAT3 in tumor progression and survival is supported by the fact that overexpression of phosphorylated STAT3 (pSTAT3) has been linked to poor prognosis in several cancers and as such, has been proposed as a relevant target for therapeutic intervention [13,14,15]
LLL12 Promotes apoptosis of canine OS lines To determine if LLL12 growth inhibition was mediated via apoptosis, canine OS cell lines were treated with DMSO or LLL12 for 24 hours, and caspase 3/7 activity was measured
Summary
STAT3 [1] has been shown to be dysregulated in nearly every major cancer, including osteosarcoma (OS). Constitutive activation of STAT3, via aberrant phosphorylation, leads to proliferation, cell survival and resistance to apoptosis. The Signal Transducers and Activators of Transcription (STATs) are a family of cell signaling proteins that play critical roles in inflammation, proliferation and differentiation [1,2,3]. STAT proteins play critical roles in responding to extracellular signals from growth factors and cytokines, as well as regulating gene transcription in the nucleus. STAT3 in particular has been shown to be dysregulated in many cancers including osteosarcoma (OS) and is frequently associated with malignant transformation and resistance to apoptosis in other tumor types [4,5,6]. The importance of STAT3 in tumor progression and survival is supported by the fact that overexpression of pSTAT3 has been linked to poor prognosis in several cancers and as such, has been proposed as a relevant target for therapeutic intervention [13,14,15]
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