College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-872, Republic of Korea.
Phytomedicine. 2016 May 15;23(5):566-77. doi: 10.1016/j.phymed.2016.02.011. Epub 2016 Feb 27.
Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division.
Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models.
The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated.
We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells.
We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment.
Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.
信号转导子和转录激活子 3（STAT3）在头颈部鳞状细胞癌（SCCHN）中持续激活，并能导致不受控制的细胞增殖和分裂。
因此，靶向阻断其活性可能是降低 SCCHN 风险的有效策略。白藜芦醇在多种癌症模型中均显示出抗癌作用。
研究了白藜芦醇对 STAT3 激活、相关蛋白激酶、磷酸酶、细胞增殖和凋亡的影响。
我们评估了白藜芦醇对 SCCHN 细胞中 STAT3 信号级联及其调节的功能反应的影响。
与其他 SCCHN 细胞相比，HN3 和 FaDu 细胞强烈表达磷酸化的 STAT3 酪氨酸 705 和丝氨酸 727 残基。白藜芦醇完全抑制 FaDu 细胞中的磷酸化，但对 HN3 细胞中的磷酸化抑制作用不明显。STAT3 抑制是通过抑制上游 JAK2 的激活介导的，但不是 JAK1 和 Src 激酶。用蛋白酪氨酸磷酸酶（PTP）抑制剂过钒酸钠处理可逆转白藜芦醇诱导的 STAT3 下调，表明 PTP 起关键作用。我们还发现白藜芦醇诱导 SOCS-1 蛋白和 mRNA 的表达。此外，通过 siRNA 敲除 SOCS-1 基因抑制 SOCS-1 的诱导，并逆转 STAT3 激活的抑制。白藜芦醇下调各种 STAT3 调节的基因产物，抑制增殖、侵袭，并导致细胞在 sub-G1 期积聚并引起细胞凋亡。此外，这种植物抗毒素与电离辐射治疗联合使用时，也显示出增强细胞凋亡的作用。
我们的结果表明，白藜芦醇通过诱导 SOCS-1 阻断 STAT3 信号通路，从而减弱 SCCHN 细胞中 STAT3 的磷酸化和增殖。
