The inhibition of thymidine phosphorylase can reverse acquired 5FU-resistance in gastric cancer cells.
The inhibition of thymidine phosphorylase can reverse acquired 5FU-resistance in gastric cancer cells.
复制标题
胸苷磷酸化酶的抑制可以逆转胃癌细胞中的5FU抗性。
DOI：
10.1007/s10120-018-0881-3
复制
发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Yamaguchi K
中科院分区：
文献类型：
--
作者：
Mori R;Yoshida K;Futamura M;Suetsugu T;Shizu K;Tanahashi T;Tanaka Y;Matsuhashi N;Yamaguchi K
5FU可以通过两种途径转化为其活性代谢物氟脱氧尿苷单磷酸（FdUMP）：乳清酸磷酸核糖基转移酶-核糖核苷酸还原酶（OPRT-RR）途径和胸苷磷酸化酶-胸苷激酶（TP-TK）途径。我们研究了 5FU 耐药的机制，重点关注 5FU 代谢的变化。 MKN45 和 5FU 耐药 MKN45/F2R 细胞用 5FU 或氟脱氧尿苷 (FdU) 联合羟基脲 (HU) 或替匹拉西 (TPI) 进行处理。 FdUMP 的量通过蛋白质印迹中胸苷酸合酶上条带的密度来确定。 MKN45/F2R 细胞表现出 5FU 耐药性（37.1 倍），并表现出 OPRT 降低和 TP 水平升高。在这两种细胞中，当 RR 被 HU 抑制时，用 5FU 处理后的 FdUMP 会降低，但当 TP 被 TPI 抑制时则不会降低。代谢组分析显示，两种细胞中细胞内脱氧核糖 1-磷酸 (dR1P) 均丢失，表明由于 dR1P 丢失，FdUMP 仅通过 OPRT-RR 途径从 5FU 合成。 TK 敲低后，MKN45 细胞中 FdU 处理后的 FdUMP 降低。然而，它在 MKN45/F2R 细胞中没有改变。此外，TP抑制导致用5FU或FdU处理后FdUMP增加，并逆转MKN45/F2R细胞中的5FU耐药性，表明MKN45/F2R细胞中FdUMP通过TP-TK途径减少。在MKN45/F2R细胞中，通过TP-TK途径减少FdUMP引起5FU耐药，而TP的抑制逆转了对5FU的耐药，表明5FU和TPI的组合是一种有前途的癌症疗法。
5FU can be converted to its active metabolite fluoro-deoxyuridine monophosphate (FdUMP) through two pathways: the orotate phosphoribosyl transferase–ribonucleotide reductase (OPRT–RR) pathway and the thymidine phosphorylase–thymidine kinase (TP–TK) pathway. We investigated the mechanism underlying 5FU-resistance, focusing on the changes in the 5FU metabolisms. MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU or fluoro-deoxyuridine (FdU) in combination with hydroxyurea (HU) or tipiracil (TPI). The amount of FdUMP was determined by the density of the upper band of thymidylate synthase on Western blotting. The MKN45/F2R cells exhibited 5FU resistance (37.1-fold) and showed decreased OPRT and increased TP levels. In both cells, the FdUMP after treatment with 5FU was decreased when RR was inhibited by HU but not when TP was inhibited by TPI. A metabolome analysis revealed the loss of intracellular deoxyribose 1-phosphate (dR1P) in both cells, indicating that FdUMP was synthesized from 5FU only through the OPRT–RR pathway because of the loss of dR1P. After the knockdown of TK, the FdUMP after treatment with FdU was decreased in MKN45 cells. However, it was not changed in MKN45/F2R cells. Furthermore, TP inhibition caused an increase in FdUMP after treatment with 5FU or FdU and reversed the 5FU resistance in MKN45/F2R cells, indicating that FdUMP was reduced through the TP–TK pathway in MKN45/F2R cells. In MKN45/F2R cells, the reduction of FdUMP through the TP–TK pathway caused 5FU resistance, and the inhibition of TP reversed the resistance to 5FU, suggesting that the combination of 5FU and TPI is a promising cancer therapy.
登录
查看更多内容
影响因子：
8.8
作者：
Evrard, A;Cuq, P;Ciccolini, J;Vian, L;Cano, JP
通讯作者：
Cano, JP
影响因子：
2.9
作者：
Mori, Ryutaro;Futamura, Manabu;Yoshida, Kazuhiro
通讯作者：
Yoshida, Kazuhiro
影响因子：
45.3
作者：
Sasako, Mitsuru;Sakuramoto, Shinichi;Ohashi, Yasuo
通讯作者：
Ohashi, Yasuo
影响因子：
3.6
作者：
Koizumi W;Kim YH;Fujii M;Kim HK;Imamura H;Lee KH;Hara T;Chung HC;Satoh T;Cho JY;Hosaka H;Tsuji A;Takagane A;Inokuchi M;Tanabe K;Okuno T;Ogura M;Yoshida K;Takeuchi M;Nakajima T;JACCRO and KCSG Study Group
通讯作者：
JACCRO and KCSG Study Group
影响因子：
9.7
作者：
Kodera, Yasuhiro;Ito, Seiji;Nakao, Akimasa
通讯作者：
Nakao, Akimasa