Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling
Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling
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DOI：
10.1186/s13046-019-1418-2
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发表时间：
2019-10-26
影响因子：
11.3
通讯作者：
Peng, Zhihai
中科院分区：
文献类型：
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作者：
Ou, Baochi;Sun, Hongze;Peng, Zhihai
polo样激酶3 （PLK3）已被证明是几种类型恶性肿瘤的肿瘤抑制因子。然而，PLK3在结直肠癌（CRC）进展和糖代谢中的作用尚不清楚。方法采用免疫组化方法检测PLK3在结直肠癌组织中的表达。用EdU、CCK-8和体内分析检测细胞增殖情况。葡萄糖代谢通过检测乳酸生成、葡萄糖摄取、线粒体呼吸、细胞外酸化速率、耗氧量和ATP生成来评估。通过染色质免疫沉淀法、荧光素酶报告基因法和共免疫沉淀法来探索信号通路。通过荧光素酶报告基因检测和与靶蛋白表达的相关性来确定mirna的特异性靶向性。结果PLK3在结直肠癌组织中显著下调，其低表达与患者预后不良相关。体外和体内实验表明，PLK3对CRC细胞的生长有抑制作用。此外，我们证明PLK3通过靶向己糖激酶2 （HK2）的表达来阻碍葡萄糖代谢。机械地，PLK3与热休克蛋白90 （HSP90）结合并促进其降解，导致磷酸化的STAT3显著减少。p-STAT3的下调进一步抑制了HK2的转录激活。此外，我们的研究表明，在CRC细胞中，miR-106b在转录后水平直接靶向PLK3。结论PLK3通过HSP90/STAT3/HK2信号通路抑制糖代谢，可能成为结直肠癌的潜在治疗靶点。
Background Polo-like kinase 3 (PLK3) has been documented as a tumor suppressor in several types of malignancies. However, the role of PLK3 in colorectal cancer (CRC) progression and glucose metabolism remains to be known. Methods The expression of PLK3 in CRC tissues was determined by immunohistochemistry. Cells proliferation was examined by EdU, CCK-8 and in vivo analyses. Glucose metabolism was assessed by detecting lactate production, glucose uptake, mitochondrial respiration, extracellular acidification rate, oxygen consumption rate and ATP production. Chromatin immunoprecipitation, luciferase reporter assays and co-immunoprecipitation were performed to explore the signaling pathway. Specific targeting by miRNAs was determined by luciferase reporter assays and correlation with target protein expression. Results PLK3 was significantly downregulated in CRC tissues and its low expression was correlated with worse prognosis of patients. In vitro and in vivo experiments revealed that PLK3 contributed to growth inhibition of CRC cells. Furthermore, we demonstrated that PLK3 impeded glucose metabolism via targeting Hexokinase 2 (HK2) expression. Mechanically, PLK3 bound to Heat shock protein 90 (HSP90) and facilitated its degradation, which led to a significant decrease of phosphorylated STAT3. The downregulation of p-STAT3 further suppressed the transcriptional activation of HK2. Moreover, our investigations showed that PLK3 was directly targeted by miR-106b at post-transcriptional level in CRC cells. Conclusion This study suggests that PLK3 inhibits glucose metabolism by targeting HSP90/STAT3/HK2 signaling and PLK3 may serve as a potential therapeutic target in colorectal cancer.