Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Int J Cancer. 2010 Jul 15;127(2):282-92. doi: 10.1002/ijc.25059.
STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10 to 55%) and bortezomib (from 5 to 70%) in MM cells. Overall, our results suggest that betulinic acid downregulates STAT3 activation through upregulation of SHP-1, and this may have potential in sensitization of STAT3 overexpressing tumors to chemotherapeutic agents.
STAT3 的激活与多种人类癌症的存活、增殖和侵袭有关。我们研究了桦木酸（一种五环三萜）是否能调节 STAT3 通路，发现桦木酸能抑制 STAT3、Src 激酶、JAK1 和 JAK2 的组成性激活。过钒酸钠逆转了桦木酸诱导的 STAT3 激活下调，表明涉及一种蛋白酪氨酸磷酸酶（PTP）。此外，桦木酸诱导 PTP SHP-1 的表达，沉默 SHP-1 基因消除了桦木酸抑制 STAT3 激活的能力，并挽救了桦木酸诱导的细胞死亡。桦木酸还下调了 STAT3 调节的基因产物的表达，如 bcl-xL、bcl-2、cyclin D1 和 survivin。这与凋亡增加有关，表现为亚 G1 细胞群增加和 caspase-3 诱导的 PARP 切割增加。与这些结果一致，组成性激活 STAT3 的过表达显著降低了桦木酸诱导的细胞凋亡。桦木酸还增强了 MM 细胞中沙利度胺（从 10%增加到 55%）和硼替佐米（从 5%增加到 70%）诱导的凋亡。总的来说，我们的结果表明，桦木酸通过上调 SHP-1 下调 STAT3 激活，这可能有助于对 STAT3 过表达肿瘤对化疗药物的敏感性。
