胸腺嘧啶磷解酶於THP-1細胞存活所扮演的角色

Abstract

胸腺嘧啶磷解酶(thymidine phosphorylase，TP)催化thymidine的磷解反應，此一反應為一可逆反應。除了參與核苷酸的代謝外，亦與血管的新生(angiogenesis)有關， TP降解Thymidine所產生的2-deoxy-ribose可以促進內皮細胞(endothelial cell)的方向性移動(directional migration)，而達到促進血管新生的功能。 TP在腫瘤細胞以及腫瘤相關巨嗜細胞(tumor-associated macrophage)中有較高的表現量，並且在腫瘤發展的過程中扮演重要的角色，藉由促進血管新生以及抑制細胞凋亡(anti-apoposis)來促進腫瘤的生長和轉移。TP在大部份正常的組織細胞中的表現量皆不高，唯獨在單核球(monocyte)、骨髓細胞(myeloid cell)以及樹突細胞(dendritic cell)等少數型態的細胞中有較高的表現量。 在本篇論文當中，我針對TP在單核性白血病(monocytic leukemia)細胞株THP-1中所可能扮演的生理功能進行探討。結果顯示，TP knockdown會造成THP-1細胞生長較為緩慢並且會有細胞死亡的現象，TP為THP-1的生長(proliferation)和存活(survival)所必須的。然而，於培養液中分別加入thymidine、2-deoxy-ribose以及thymine，並無法回復TP knockdown所造成的細胞死亡，顯示TP可能並非藉由參與dTTP以及Thymidine的代謝，而是其他的方式來促進THP-1細胞的生長與存活。

Thymidine phosphorylase (TP) catalyses the reversible phospholysis of thymidine. In addition to its role in nucleotide metabolism, TP is also an angiogenic factor. Its catabolic product, 2-deoxy-ribose produced by phospholysis of thymidine, induces directional migration of endothelial cells in vitro and angiogenesis in vivo. It has been shown that the expression of TP is elevated in solid tumor and tumor-associated macrophage. TP may promote tumor progression by inducing angiogenesis and inhibiting aopotosis of tumor cells. The expression level of TP in most normal tissues is very low. But only in monocytes, myeloid and dendritic cells, TP is highly expressed. In this study, I investigated the role of TP in monocytic leukemia cell line ,THP-1. By silencing of TP expression, we found that TP knockdown induces growth retardation and cell death, indicating that TP is necessary for the proliferation and survival of THP-1 cells. However, the cell death induced by TP knockdown was not reversed by either thymidine , 2-deoxy-ribose, or thymine, suggesting its survival role other than its metabolic functions in dTTP synthesis.