Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030, USA.
Mol Cancer Res. 2010 Jan;8(1):107-18. doi: 10.1158/1541-7786.MCR-09-0257. Epub 2010 Jan 12.
The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with carcinogenesis through survival, proliferation, and angiogenesis of tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of cancer. In the present report, we investigated whether 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), an analogue of vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that plumbagin inhibited both constitutive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation. Vanadate, however, reversed the plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that plumbagin induced the expression of the protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of plumbagin. This agent also downregulated the expression of STAT3-regulated cyclin D1, Bcl-xL, and vascular endothelial growth factor; activated caspase-3; induced poly (ADP ribose) polymerase cleavage; and increased the sub-G(1) population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the plumbagin-induced apoptosis. When compared with AG490, a rationally designed STAT3/JAK2 inhibitor, plumbagin was found more potent in suppressing the proliferation of cells. Plumbagin also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. Overall, these results suggest that the plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents.
信号转导子和转录激活子 3（STAT3）的激活已通过肿瘤细胞的存活、增殖和血管生成与致癌作用相关联。能够抑制 STAT3 激活的试剂不仅具有预防作用，而且具有治疗癌症的潜力。在本报告中，我们研究了 5-羟基-2-甲基-1,4-萘醌（萘醌），一种维生素 K 的类似物，是否可以调节 STAT3 途径。我们发现，萘醌抑制多发性骨髓瘤（MM）细胞中组成型和白细胞介素 6 诱导的 STAT3 磷酸化，这与 c-Src、Janus 激活激酶（JAK）1 和 JAK2 激活的抑制相关。然而，钒酸盐逆转了萘醌诱导的 STAT3 激活的下调，表明涉及蛋白酪氨酸磷酸酶。事实上，我们发现萘醌诱导蛋白酪氨酸磷酸酶 SHP-1 的表达，并且 SHP-1 的沉默消除了萘醌的作用。该试剂还下调 STAT3 调节的细胞周期蛋白 D1、Bcl-xL 和血管内皮生长因子的表达；激活半胱天冬酶-3；诱导聚（ADP 核糖）聚合酶裂解；并增加 MM 细胞的亚 G1 群体。与这些结果一致，组成型激活 STAT3 的过表达显著降低了萘醌诱导的细胞凋亡。与合理设计的 STAT3/JAK2 抑制剂 AG490 相比，发现萘醌在抑制细胞增殖方面更有效。萘醌还显著增强了 MM 细胞中沙利度胺和硼替佐米的凋亡作用。总体而言，这些结果表明，萘醌通过诱导 SHP-1 抑制 STAT3 激活途径，这可能介导 STAT3 过表达癌症对化疗药物的敏感性。
