Ginkgolic acid C 17:1 (GAC 17:1) extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s) through modulation of several molecular targets in tumor cells, however the detailed mechanism(s) of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP) inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion of PTEN and SHP-1 genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.

中文翻译：

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Ginkgolic Acid C 17:1，源自银杏叶，通过诱导 PTEN 和 SHP-1 酪氨酸磷酸酶抑制组成型和诱导型 STAT3 激活

从银杏叶中提取的银杏酸 C 17:1 (GAC 17:1) 先前已被报道通过调节肿瘤细胞中的几个分子靶标表现出多种抗肿瘤作用，但其作用的详细机制仍有待阐明。信号转导和转录激活因子 3 (STAT3) 是一种致癌转录因子，可调节参与多种血液系统恶性肿瘤（包括多发性骨髓瘤）进展的各种关键功能，因此减弱 STAT3 激活可能在癌症治疗中具有潜力。我们确定了 GAC 17:1 在多发性骨髓瘤细胞系中对 STAT3 信号通路的影响的抗肿瘤机制。我们发现 GAC 17:1 可以通过取消上游 JAK2 来抑制 STAT3 的组成型激活，Src 而不是 U266 细胞中的 JAK1 激酶，还发现 GAC 可以抑制 MM.1S 细胞中 IL-6 诱导的 STAT3 磷酸化。蛋白酪氨酸磷酸酶 (PTP) 抑制剂的处理阻止了 GAC 17:1 对 STAT3 磷酸化的抑制，从而表明 PTP 的关键作用。我们还证明 GAC 17:1 可以在蛋白质和 mRNA 水平诱导 PTEN 和 SHP-1 的大量表达。此外，通过siRNA删除PTEN和SHP-1基因可以抑制PTEN和SHP-1的诱导，并消除药物对STAT3磷酸化的抑制作用。GAC 17:1 下调 STAT3 调节基因产物的表达并诱导肿瘤细胞凋亡。总体而言，发现 GAC 17:1 可以消除 STAT3 信号通路，从而对多发性骨髓瘤细胞发挥抗癌作用。