FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.
FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.
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DOI：
10.1186/s12885-016-2057-z
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发表时间：
2016-01-16
期刊：
影响因子：
3.8
通讯作者：
Nikfarjam M
中科院分区：
文献类型：
--
作者：
Yeo D;He H;Patel O;Lowy AM;Baldwin GS;Nikfarjam M
胰腺导管腺癌仍然是所有实体瘤中最致命的肿瘤之一。治疗选择有限，基于吉西他滨的化疗仍然是标准治疗。虽然越来越多的证据表明p21激活激酶1（PAK 1）在胰腺癌中起着至关重要的作用，但其作用尚未完全阐明。本研究旨在探讨PAK 1在胰腺癌中的表达及其功能相关性。PAK 1的表达在胰腺癌标本通过免疫组织化学和胰腺癌细胞系通过蛋白质印迹法进行测量。分别通过胸苷摄取和Boyden室测定来测量通过shRNA敲低（KD）或通过选择性抑制剂FRAX 597单独或与吉西他滨组合来抑制PAK 1对细胞增殖和迁移/侵袭的影响。在原位小鼠模型中评估对肿瘤生长和存活的影响。PAK 1在所有检测的人胰腺癌样品中表达，并且在所有检测的胰腺癌细胞系中上调。PAK 1 KD抑制胰腺癌细胞生长和存活，并增加对吉西他滨治疗的敏感性。AKT活性和HIF 1 α表达也受到抑制。FRAX 597抑制胰腺癌细胞增殖、存活和迁移/侵袭。当与吉西他滨联合使用时，FRAX 597在体外协同抑制胰腺癌增殖，并在体内抑制肿瘤生长。这些结果暗示PAK 1是胰腺癌细胞生长和存活的调节因子。PAK 1抑制剂如FRAX 597与细胞毒性化疗的组合作为胰腺癌治疗的新治疗方法值得进一步研究。本文的在线版本（doi：10.1186/s12885-016-2057-z）包含补充材料，可供授权用户使用。
Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1α expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo. These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment. The online version of this article (doi:10.1186/s12885-016-2057-z) contains supplementary material, which is available to authorized users.