Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou 310006, China.
Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Toxicol Appl Pharmacol. 2020 Dec 1;408:115273. doi: 10.1016/j.taap.2020.115273. Epub 2020 Oct 6.
Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.
鉴于不可切除的晚期胃癌（GC）预后不良，需要新的治疗策略。丝裂原活化蛋白激酶（MAPK）信号级联反应是 GC 中最常被激活的途径，在肿瘤发生和转移中发挥重要作用。MAPK/细胞外信号调节激酶（ERK）途径是 GC 的一个有吸引力的治疗靶点。在这项研究中，MEK 抑制剂曲美替尼降低了 GC 细胞中的 p-ERK 水平，并显著增加了信号转导和转录激活因子 3（STAT3）的磷酸化，导致对曲美替尼的敏感性降低。来自植物酸浆Physalis pubescens L. 的甾体化合物 physapubescin B（PB）通过抑制 STAT3 磷酸化来抑制 GC 细胞的增殖并诱导其凋亡。PB 和 trametinib 的联合抑制了 trametinib 诱导的 STAT3 磷酸化，并在体外和体内协同抑制胃肿瘤生长。总之，这些结果表明抑制 MEK 和 STAT3 可能对 MAPK/ERK 通路依赖的 GC 患者有效。
