甘胺酸螯合鐵透過抑制低氧誘導因子-1 alpha反轉人類惡性膠質瘤細胞的上皮間質細胞轉移

過去有許多研究證實低氧誘導因子-1 alpha (HIF-1 alpha) 與癌症的代謝、轉移、侵襲和抗藥性有密切的相關。本篇研究發現在人類惡性膠質瘤中，甘胺酸螯合鐵 (ferrous glycinate) 可以透過增進與VHL的結合而促進低氧誘導因子-1的降解。甘胺酸螯合鐵透過減少HIF-1的堆積，可減少腦瘤細胞中的侵襲及轉移，也減少了基質金屬蛋白酶2和9 (matrix metalloproteinase-2/9, MMP-2/9) 的分泌。在蛋白層面，甘胺酸螯合鐵也減少了腦瘤細胞的轉錄因子扭轉蛋白 (twist) ，及其下游的波形蛋白 (vimentin) 之表現量減少，進而減少了會誘導上皮間質細胞轉移的現象。此外，甘胺酸螯合鐵亦可減少膠質細胞未分化狀態的巢蛋白 (nestin) ，並同時增加已分化的膠質原纖維酸蛋白 (glial fibrillary acidic protein, GFAP) ，促進其膠質瘤的分化。因此甘胺酸螯合鐵可能可以反轉上皮間質細胞轉移的現象，但與骨橋蛋白 (osteopontin, OPN) 和節點 (nodal) 關聯性不大。另外，我們發現甘胺酸螯合鐵調控HIF-1 alpha的機制並無改善華堡效應的結果，而合併使用甘胺酸螯合鐵及腦瘤的第二線治療用藥：卡莫司汀 (carmustine, BCNU) 及 (temolozomide, TMZ) ，對於改善腦瘤細胞對其所產生抗藥性問題的幫助也並不大。綜合以上結果，甘胺酸螯合鐵可能可以改善人類惡性膠質瘤細胞的上皮間質細胞轉移的現象。

關鍵字

低氧誘導因子-1 alpha ；甘胺酸螯合鐵；人類惡性膠質瘤細胞；上皮間質細胞轉移

並列摘要

Hypoxia-inducible factor (HIF)-1 alpha has been shown to play important roles in regulating cancer metabolism, metastasis, invasion and drug resistant. In the present study, we showed that treatment of human U87 glioma cells with ferrous glycinate reduced HIF-1 alpha accumulation, which is dependent upon prolyl hydroxylase activity. The effect was more important and obviously in cancer metastasis and invasion. Suppression of HIF-1 alpha by ferrous glycinate reduced MMP-2 and MMP-9 secretion in the media. Ferrous glycinate decreased the expression of transcription factors twist and nestin, and the mesenchymal marker, vimentin. Consistently, ferrous glycinate increased expression of differentiation marker, the glial acidic fibrillary protein (GFAP). Taken together, these suggest that ferrous glycinate may reverse the epithelial-mesenchymal transition but not associated with osteopontin (OPN) or nodal. In addition, the present study shown that ferrous glycinate did not alter aerobic glycolysis, which also called warburg effect in human glioma cells. On the other hand, treatment with ferrous glycinate did not increase the sensitivity of glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temolozomide (TMZ), chemotherapeutic agents for malignant gliomas. In conclusion, our results suggest that treatment with ferrous glycinate reversed the EMT and decreased cell invasiveness in malignant gliomas cells.

並列關鍵字

HIF-1 alpha ； ferrous glycinate ； human U87 glioma cells ； EMT

參考文獻

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甘胺酸螯合鐵透過抑制低氧誘導因子-1 alpha反轉人類惡性膠質瘤細胞的上皮間質細胞轉移

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