The double inhibition of PDK1 and STAT3-Y705 prevents liver metastasis in colorectal cancer
The double inhibition of PDK1 and STAT3-Y705 prevents liver metastasis in colorectal cancer
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PDK1和STAT3-Y705双重抑制可预防结直肠癌肝转移
DOI：
10.1038/s41598-019-49480-8
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发表时间：
2019-09-10
影响因子：
4.6
通讯作者：
Wei, Shaozhong
中科院分区：
文献类型：
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作者：
Qin, Wenjuan;Tian, Yun;Wei, Shaozhong
丙酮酸脱氢酶激酶1 （pyruvate dehydrogenase kinase 1, PDK1）作为一种关键的糖酵解酶，在结直肠癌（CRC）发生发展中的意义尚不清楚。本研究发现，高水平PDK1的CRC患者预后较差，PDK1敲低可显著降低裸鼠和免疫能力强的BALB/C小鼠的CRC肝转移。当与STAT3-p-Y705抑制剂隐丹参酮（CPT）联合使用时，进一步抑制了肝转移。PDK1敲低明显增加了anoikis条件下的活性氧水平，随后导致anoikis升高，但PDK1敲低和CPT联合使用对anoikis的影响减弱。基于这一差异，我们进一步检测了结直肠癌细胞对基质蛋白纤维连接蛋白的粘附能力。结果表明，PDK1敲低与CPT联合使用可显著降低CRC细胞对纤维连接蛋白的粘附性。这些结果表明，抑制PDK1可以通过上调anoikis来减少CRC细胞在血液循环中的存活，抑制STAT3-p-Y705可以阻止其在肝脏转移前生态位定居，最终减少肝转移。
As a key glycolysis enzyme, the significance of pyruvate dehydrogenase kinase 1 (PDK1) in the development of colorectal cancer (CRC) remains unknown. This study revealed that the prognosis of CRC patients with high levels of PDK1 was poor, and PDK1 knockdown significantly reduced liver metastasis of CRC in both nude mice and immune competent BALB/C mice. When combined with cryptotanshinone (CPT), an inhibitor of STAT3-p-Y705, the liver metastasis was further inhibited. PDK1 knockdown obviously increased reactive oxygen species level in anoikis conditions and subsequently resulted in an elevated anoikis, but the combination of PDK1 knockdown and CPT showed a reduced effect on anoikis. Based on this discrepancy, the adherence ability of CRC cells to matrix protein fibronectin was further detected. It showed that PDK1 knockdown significantly decreased the adherence of CRC cells to fibronectin when combined with CPT. These results suggest that inhibition of PDK1 can decrease the surviving CRC cells in blood circulation via up-regulation of anoikis, and inhibition of STAT3-p-Y705 can prevent it to settle down on the liver premetastatic niche, which ultimately reduces liver metastasis.