College of Korean Medicine, Kyung Hee University, Seoul, Republic of, Korea.
Mol Carcinog. 2014 Oct;53(10):793-806. doi: 10.1002/mc.22035. Epub 2013 Jun 13.
Constitutive activation of STAT3 is frequently observed and closely linked with proliferation, survival, invasion, metastasis and angiogenesis in tumor cells. In the present study, we investigated whether β-caryophyllene oxide (CPO), a sesquiterpene isolated primarily from the essential oils of medicinal plants such as guava (Psidium guajava), and oregano (Origanum vulgare L.), can mediate its effect through interference with the STAT3 activation pathway in cancer cells. The effect of CPO on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different tumor cell lines. We found that CPO suppressed constitutive STAT3 activation in multiple myeloma (MM), breast and prostate cancer cell lines, with a significant dose- and time-dependent effects observed in MM cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src and JAK1/2. Also, vanadate treatment reversed CPO-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that CPO induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of CPO to inhibit STAT3 activation. The inhibition of STAT3 activation by CPO inhibited proliferation, induced apoptosis and abrogated the invasive potential of tumor cells. Our results suggest for the first time that CPO is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of various cancers harboring constitutively activated STAT3.
STAT3 的组成性激活经常在肿瘤细胞中观察到，并且与增殖、存活、侵袭、转移和血管生成密切相关。在本研究中，我们研究了 β-石竹烯氧化物（CPO），一种主要从药用植物如番石榴（Psidium guajava）和牛至（Origanum vulgare L.）的精油中分离出来的倍半萜烯，是否可以通过干扰癌细胞中的 STAT3 激活途径来发挥其作用。使用功能蛋白质组肿瘤通路技术平台和不同的肿瘤细胞系研究了 CPO 对 STAT3 激活、相关蛋白激酶和磷酸酶、STAT3 调节的基因产物和细胞凋亡的影响。我们发现 CPO 抑制多发性骨髓瘤（MM）、乳腺癌和前列腺癌细胞系中的组成性 STAT3 激活，在 MM 细胞中观察到明显的剂量和时间依赖性效应。抑制作用是通过抑制上游激酶 c-Src 和 JAK1/2 的激活介导的。此外，钒酸盐处理逆转了 CPO 诱导的 STAT3 下调，表明涉及酪氨酸磷酸酶。事实上，我们发现 CPO 诱导了酪氨酸磷酸酶 SHP-1 的表达，这与组成性 STAT3 激活的下调相关。有趣的是，通过 siRNA 敲除 SHP-1 基因消除了 CPO 抑制 STAT3 激活的能力。CPO 抑制 STAT3 激活抑制增殖、诱导凋亡并削弱肿瘤细胞的侵袭潜力。我们的研究结果首次表明，CPO 是 STAT3 信号级联的新型阻断剂，因此在治疗各种含有组成性激活 STAT3 的癌症方面具有巨大潜力。
