Lin Lin, Ding Dapeng, Jiang Yanmei, Li Yan, Li Shijun
Department of Clinical Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, China.
Oncogenesis. 2018 Sep 7;7(9):67. doi: 10.1038/s41389-018-0078-y.
Mutations in BRAF are common to many cancers, including CRC. The MEK inhibitors are being investigated in BRAF-mutant CRC. In this study, we aimed to investigate how MEK inhibitor suppresses growth of BRAF-mutated CRC cells as well as its potential mechanisms. Our findings indicated that MEK inhibitor promote PUMA expression via ERK/FoxO3a signaling pathway. In addition, PUMA induction is essential for MEK inhibitor-induced apoptosis. Moreover, PUMA induction is required for MEK inhibitors to induced apoptosis in combination with cisplatin, dabrafenib, or Gefitinib. Knockdown of PUMA suppressed the anticancer effect of the MEK inhibitor in vivo. Our findings indicate a novel role for PUMA as a regulator of the antitumor effects of MEK inhibitor, suggesting that PUMA induction may modulate MEK inhibitor sensitivity.
BRAF 突变在包括结直肠癌（CRC）在内的多种癌症中很常见。MEK 抑制剂正在 BRAF 突变的结直肠癌中进行研究。在本研究中，我们旨在探讨 MEK 抑制剂如何抑制 BRAF 突变的结直肠癌细胞生长及其潜在机制。我们的研究结果表明，MEK 抑制剂通过 ERK/FoxO3a 信号通路促进 PUMA 表达。此外，PUMA 的诱导对于 MEK 抑制剂诱导的细胞凋亡至关重要。而且，MEK 抑制剂与顺铂、达拉非尼或吉非替尼联合诱导细胞凋亡需要 PUMA 的诱导。敲低 PUMA 可抑制 MEK 抑制剂在体内的抗癌作用。我们的研究结果表明，PUMA 作为 MEK 抑制剂抗肿瘤作用的调节因子具有新的作用，提示 PUMA 的诱导可能调节 MEK 抑制剂的敏感性。
