Abstract
Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.
Highlights
Signal transducer and activator of transcription 3 (STAT3) protein is a latent cytoplasmic transcription factor that transmits signals from the cell surface to the nucleus when activated by cytokines and growth factors [1]
As STAT 3 is constitutively activated in a wide range of malignancies, we first analyzed the mRNA expression of JAK-2 and STAT-3 by quantitative RT-PCR analysis
Our results revealed that dietary supplementation of astaxanthin significantly reduced the mRNA expression of key molecules involved In JAK/ STAT signaling compared to DMBA-painted animals (Figure 1A)
Summary
Signal transducer and activator of transcription 3 (STAT3) protein is a latent cytoplasmic transcription factor that transmits signals from the cell surface to the nucleus when activated by cytokines and growth factors [1]. Interleukin-6 (IL-6) or epidermal growth factor (EGF) stimulate the phosphorylation of STAT3 protein by Janus kinase and activated STAT3 forms a homodimer that translocates to the nucleus where it regulates the expression of genes critical for normal cellular processes such as cell development, differ-entiation, proliferation, survival, angiogenesis, and immune function [2,3,4,5,6]. Aberrant activation of JAK/STAT3 signaling has been documented in a wide variety of human tumors, including hematopoietic malignancies and solid tumors such as head and neck, breast, and prostate cancers [7,8]. Astaxanthin was found to exhibit the highest antioxidant activity among the carotenoids and is widely used in the prevention and treatment of various diseases [17]. AXT has been demonstrated to exhibit anti-inflammatory and anticancer properties [18,19]
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