Protein kinase D1 regulates hypoxic metabolism through HIF-1 and glycolytic enzymes incancer cells
Protein kinase D1 regulates hypoxic metabolism through HIF-1 and glycolytic enzymes incancer cells
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DOI：
10.3892/or.2018.6479
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发表时间：
2018-08-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Ping
中科院分区：
文献类型：
--
作者：
Chen, Jiao;Cui, Bomiao;Zhang, Ping
蛋白激酶D1（PKD 1）是蛋白激酶D（PKD）家族成员之一，在肿瘤细胞的多种生物学行为中发挥重要作用。低pH和缺氧是肿瘤微环境的独特特征。本研究旨在探讨PKD 1在低氧条件下对人舌鳞癌细胞株SCC 25代谢、生长和凋亡的调控作用及其机制。在此，我们发现缺氧不仅诱导HIF-1的表达，而且还诱导PKD 1的表达和激活。通过shRNA干扰抑制PKD 1的表达，可明显抑制SCC 25细胞在缺氧条件下的生长，降低HIF-1的表达，增加SCC 25细胞的凋亡率。此外，在低氧条件下，SCC 25细胞中PKD 1的稳定沉默降低葡萄糖摄取、乳酸产生和糖酵解酶（GLUT-1和LDHA）表达，以及降低p38 MAPK的磷酸化。结果表明，在低氧条件下抑制PKD 1的表达后，SCC 25细胞的生长和代谢受到显著抑制。相反，当PKD 1在SCC 25细胞中过表达时，结果完全逆转，除了生长和凋亡。综上所述，我们的研究结果表明，PKD 1不仅通过调节HIF-1和糖酵解酶的表达来调节癌细胞的缺氧糖酵解代谢，而且还参与了酸性肿瘤微环境的重塑。本研究提示PKD 1可能成为微环境导向肿瘤生物治疗的潜在靶点。
Protein kinase D1 (PKD1), one of the protein kinase D (PKD) family members, plays a prominent role in multiple bio-behaviors of cancer cells. Low pH and hypoxia are unique characteristics of the tumor microenvironment. The aim of this study was to investigate the role and mechanism of PKD1 in regulating metabolism in the human tongue squamous cell carcinoma (TSCC) cell line SCC25 under a hypoxic condition, as well as growth and apoptosis. Here, we found that hypoxia not only induced the expression of HIF-1, but also induced the expression and activation of PKD1. Moreover, we inhibited the expression of PKD1 by shRNA interference, and the growth of SCC25 cells under hypoxia was significantly decreased, as well as the expression of HIF-1, while the percentage of apoptotic SCC25 cells was increased. Furthermore, stable silencing of PKD1 in SCC25 cells under a hypoxic condition decreased glucose uptake, lactate production and glycolytic enzyme (GLUT-1 and LDHA) expression, as well as reduced the phosphorylation of p38 MAPK. The results revealed that following inhibition of the expression of PKD1 under a hypoxic condition, the growth and metabolism of the SCC25 cells were significantly suppressed. In contrast, when PKD1 was overexpressed in SCC25 cells, the results were completely reversed, except for growth and apoptosis. Taken together, our results demonstrated that PKD1 not only regulates the hypoxic glycolytic metabolism of cancer cells via regulation of the expression of HIF-1 and glycolytic enzymes, but is also involved in the remodeling of the acidic tumor microenvironment. This study suggests that PKD1 may be a potential target for microenvironment-directed tumor biotherapy.