Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells.
Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells.
复制标题
DOI：
10.1158/0008-5472.can-08-4323
复制
发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Xin H;Zhang C;Herrmann A;Du Y;Figlin R;Yu H
新型多靶点酪氨酸激酶抑制剂Sunitinib被用作抗血管生成剂，用于治疗几种类型的癌症，包括转移性肾细胞癌(RCC)。研究表明，舒尼替尼能明显改变肾癌患者的免疫抑制表型。为了提高其抗肿瘤效果，并为其与其他药物的联合应用提供策略，充分阐明其作用机制是至关重要的。我们发现，舒尼替尼诱导肾癌肿瘤细胞凋亡和生长停滞，这与抑制STAT3活性有关。孙尼替尼对肿瘤细胞的直接作用与von Hippel-Lindau肿瘤抑制基因状态和低氧诱导转录因子-2α水平无关。STAT3活性的降低增强了舒尼替尼的抗肿瘤作用，而结构性激活的STAT3突变体的表达拯救了肿瘤细胞的死亡。活体多光子显微镜数据显示，在肿瘤血管崩溃之前，舒尼替尼在体内诱导了小鼠Renca肿瘤细胞的凋亡。舒尼替尼还抑制Renca肿瘤相关髓系衍生抑制细胞(MDSCs)中的STAT3，下调血管生成基因的表达，并减少MDSCs和肿瘤T调节细胞。这些结果表明，STAT3活性在肾癌对舒尼替尼的反应中起重要作用，抑制STAT3使其对肿瘤细胞具有直接促凋亡活性，并对肿瘤免疫微环境产生积极作用。
The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an anti-angiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. In order to improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with Stat3 activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances sunitinib’s antitumor effects, whereas expression of a constitutively-activated Stat3 mutant rescues tumor cell death. Intravital multi-photon microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor–associated myeloid derived suppressor cells (MDSCs), downregulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits sunitinib’s direct proapoptotic activity on tumor cells and positive effects on tumor immunologic microenvironment.