在人類肺癌細胞中甘胺酸螯合鐵透過抑制低氧誘導因子來調控細胞的能量代謝及侵襲性

Ferrous glycinate regulates cell energy metabolism and invasiveness via suppression of hypoxia-induced factor in human A549 cells

鄭仲惠(Jhong-Huei Jheng)

指導教授 ： 李宏謨

臺北醫學大學/醫學科技學院/醫學檢驗暨生物技術學系所/碩士(2016年)

摘要

低氧誘導因子(Hypoxia-inducible factor 1 alpha, HIF-1α) 在實質性腫瘤的缺氧微環境中扮演重要角色，調控了癌細胞的增殖，遷移性和侵襲性。而在目前的研究結果中，我們發現甘胺酸螯合鐵會透過活化脯氨酰羥化酶(prolyl hydroxylase)降低HIF-1α的蛋白表現量，進而調控葡萄糖轉運蛋白(Glucose transporter-1, Glut-1)、己糖激酶(hexokinase-2)、乳酸脫氫酶(lactate dehydrogenase A, LDHA)而降低有氧醣解作用。另一方面，也減少了丙酮酸脫氫酶激酶(pyruvate dehydrogenase kinase, PDK)的蛋白表現量及丙酮酸脫氫酶(pyruvate dehydrogenase, PDH)的磷酸化，進而增加粒線體膜電位和ATP的產生，因此推測甘胺酸螯合鐵可能反轉了癌細胞的瓦氏效應(Warburg effect)。此外也發現甘胺酸螯合鐵能夠減少Twist蛋白量，導致增加E-cadherin蛋白量及減少Vimentin蛋白量，改善了癌細胞的上皮細胞間質轉化現象，進而抑制細胞的遷移速度及侵襲性。這些結果表示甘胺酸螯合鐵可能可以成為治療人類肺腺癌的佐劑。

關鍵字

低氧誘導因子 ； 瓦氏效應 ； 甘胺酸螯合鐵 ； 能量代謝 ； 細胞侵襲性

並列摘要

HIF-1α is a multi-facet protein that control tumor progression, including cell proliferation, invasion and metastasis. In the present study, we demonstrated that incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α through a prolyl hydroxylation-dependent mechanism. The reduction of HIF-1α level was associated with decreased expression levels of glucose transporter, Glut-1, and glycolytic enzymes including hexokinase-2, and lactate dehydrogenase A. On the other hand, treatment with ferrous glycinate reactivated oxidative phosphorylation by decreasing the expression of pyruvate dehydrogenase kinase-1 and pyruvate dehydrogenase phosphorylation that subsequently increased mitochondrial membrane potential and ATP production, suggesting ferrous glycinate may reverse Warburg effect. In addition, ferrous glycinate decreased cell migration and invasion in A549 cells, which was accompanied with reduced twist and vimentin protein levels and increased of E-cadherin, suggesting ferrous glycinate may alter the epithelial mesenchymal transition. These results indicate that ferrous glycinate may serve as a therapeutic adjuvant for human lung adenocarcinoma.

並列關鍵字

HIF-1α ； Warburg effec ； ferrous glycinate ； energy metabolism ； cell invasiveness

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