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The double inhibition of PDK1 and STAT3-Y705 prevents liver metastasis in colorectal cancer.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-09-10 , DOI: 10.1038/s41598-019-49480-8 Wenjuan Qin 1 , Yun Tian 2 , Jing Zhang 3 , Wenjian Liu 4 , Qiming Zhou 5 , Sheng Hu 3 , Fei Yang 6 , Li Lu 7 , Haijie Lu 1 , Shuzhong Cui 2 , Lu Wen 8 , Shaozhong Wei 7
Scientific Reports ( IF 3.8 ) Pub Date : 2019-09-10 , DOI: 10.1038/s41598-019-49480-8 Wenjuan Qin 1 , Yun Tian 2 , Jing Zhang 3 , Wenjian Liu 4 , Qiming Zhou 5 , Sheng Hu 3 , Fei Yang 6 , Li Lu 7 , Haijie Lu 1 , Shuzhong Cui 2 , Lu Wen 8 , Shaozhong Wei 7
Affiliation
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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.
中文翻译：
PDK1和STAT3-Y705的双重抑制可防止大肠癌的肝转移。
作为一种关键的糖酵解酶，丙酮酸脱氢酶激酶1（PDK1）在结直肠癌（CRC）发生中的意义仍然未知。这项研究表明，高PDK1水平的CRC患者的预后很差，而PDK1敲低显着降低了裸鼠和具有免疫能力的BALB / C小鼠的CRC肝转移。当与STAT3-p-Y705抑制剂隐丹参酮（CPT）结合使用时，肝转移被进一步抑制。PDK1组合式明显降低了在缺氧条件下的活性氧水平，并随后导致了较高的缺氧，但是PDK1组合式和CPT的组合显示出对缺氧的降低的作用。基于该差异，进一步检测了CRC细胞对基质蛋白纤连蛋白的粘附能力。结果表明，与CPT结合使用时，PDK1的敲低显着降低了CRC细胞对纤连蛋白的粘附。这些结果表明，PDK1的抑制可通过上清液的上调来减少血液循环中存活的CRC细胞，而STAT3-p-Y705的抑制则可防止其在肝转移前的环境中稳定下来，从而最终减少肝转移。
更新日期：2019-09-10
中文翻译：
PDK1和STAT3-Y705的双重抑制可防止大肠癌的肝转移。
作为一种关键的糖酵解酶，丙酮酸脱氢酶激酶1（PDK1）在结直肠癌（CRC）发生中的意义仍然未知。这项研究表明，高PDK1水平的CRC患者的预后很差，而PDK1敲低显着降低了裸鼠和具有免疫能力的BALB / C小鼠的CRC肝转移。当与STAT3-p-Y705抑制剂隐丹参酮（CPT）结合使用时，肝转移被进一步抑制。PDK1组合式明显降低了在缺氧条件下的活性氧水平，并随后导致了较高的缺氧，但是PDK1组合式和CPT的组合显示出对缺氧的降低的作用。基于该差异，进一步检测了CRC细胞对基质蛋白纤连蛋白的粘附能力。结果表明，与CPT结合使用时，PDK1的敲低显着降低了CRC细胞对纤连蛋白的粘附。这些结果表明，PDK1的抑制可通过上清液的上调来减少血液循环中存活的CRC细胞，而STAT3-p-Y705的抑制则可防止其在肝转移前的环境中稳定下来，从而最终减少肝转移。
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