Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer
Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer
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DOI：
10.1111/cas.12080
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发表时间：
2013-03-01
期刊：
影响因子：
5.7
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Takahashi, Ryota;Hirata, Yoshihiro;Koike, Kazuhiko
c-Jun N-末端激酶（JNK）是丝裂原活化蛋白激酶（MAPK）家族的成员，并且据报道其参与多种癌症的发展。然而，JNK在胰腺癌中的作用尚未阐明。我们评估了JNK在胰腺癌发展中的作用，并研究了JNK抑制剂对这种致命癌症的治疗效果。针对JNK或JNK抑制剂SP 600125的小干扰RNA被用于检测JNK在胰腺癌细胞系的细胞增殖和细胞周期中的作用。用JNK抑制剂处理Ptf 1acre/+; LSL-KrasG 12 D/+; Tgfbr 2flox/flox小鼠，以检查胰腺组织学和存活率。JNK抑制对肿瘤血管生成的影响也使用细胞系和鼠胰腺癌标本进行了评估。JNK在人和小鼠胰腺癌中在体外和体内经常被激活。人胰腺癌细胞系的生长受到抑制JNK抑制通过G1期阻滞在细胞周期中减少cyclin D1的表达。此外，致癌K-ras表达导致胰腺癌细胞系中JNK的激活。Ptf 1acre/+处理; LSL-KrasG12D/+; Tgfbr 2flox/flox小鼠与JNK抑制剂减少小鼠胰腺癌的生长和延长小鼠的生存期显着。在体外和体内，JNK抑制也降低了血管生成。结论：JNK的激活促进胰腺癌的发生发展，JNK可能是胰腺癌治疗的一个潜在靶点。
c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family, and it is reportedly involved in the development of several cancers. However, the role of JNK in pancreatic cancer has not been elucidated. We assessed the involvement of JNK in the development of pancreatic cancer and investigated the therapeutic effect of JNK inhibitors on this deadly cancer. Small interfering RNAs against JNK or the JNK inhibitor SP600125 were used to examine the role of JNK in cellular proliferation and the cell cycles of pancreatic cancer cell lines. Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox mice were treated with the JNK inhibitor to examine pancreatic histology and survival. The effect of JNK inhibition on tumor angiogenesis was also assessed using cell lines and murine pancreatic cancer specimens. JNK was frequently activated in human and murine pancreatic cancer in vitro and in vivo. Growth of human pancreatic cancer cell lines was suppressed by JNK inhibition through G1 arrest in the cell cycle with decreased cyclin D1 expression. In addition, oncogenic K-ras expression led to activation of JNK in pancreatic cancer cell lines. Treatment of Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox mice with the JNK inhibitor decreased growth of murine pancreatic cancer and prolonged survival of the mice significantly. Angiogenesis was also decreased by JNK inhibition in vitro and in vivo. In conclusion, activation of JNK promotes development of pancreatic cancer, and JNK may be a potential therapeutic target for pancreatic cancer.