Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance.
5-Fluorouracil (5-FU) continues to be widely used for treatment of gastrointestinal cancers. Because many tumors show primary or acquired resistance, it is important to understand the molecular basis underlying the mechanism of resistance to 5-FU. In addition to its effect on thymidylate synthase inhibition and DNA synthesis, 5-FU may also influence RNA metabolism. Our previous studies revealed that colorectal cancer cells resistant to bolus 5-FU (HCT-8/4hFU) showed significantly decreased incorporation of the drug into RNA. Resistance to bolus 5-FU was associated with lower expression of UMP kinase (UMPK), an enzyme that plays an important role in the activation of 5-FU to 5-FUTP and its incorporation into RNA. Activities of other 5-FU-metabolizing enzymes (e.g., thymidine kinase, uridine phosphorylase, thymidine phosphorylase, and orotate phosphoribosyltransferase) remained unchanged between sensitive and resistant cell lines. Herein, we show that UMPK down-regulation in 5-FU-sensitive cells (HCT-8/P) induces resistance to bolus 5-FU treatment. Moreover, HCT-8/4hFU cells are even more cross-resistant to treatment with 5-fluorouridine, consistent with the current understanding of 5-fluorouridine as a RNA-directed drug. Importantly, colorectal cancer hepatic metastases isolated from patients clinically resistant to weekly bolus 5-FU/leucovorin treatment exhibited decreased mRNA expression of UMPK but not thymidylate synthase or dihydropyrimidine dehydrogenase compared with tumor samples of patients not previously exposed to 5-FU. Our findings provide new insights into the mechanisms of acquired resistance to 5-FU in colorectal cancer and implicate UMPK as an important mechanism of clinical resistance to pulse 5-FU treatment in some patients.
Humeniuk
Rita
R
The Graduate School of Biomedical Sciences, Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08903, USA.
Menon
Lata G
LG
Mishra
Prasun J
PJ
Gorlick
Richard
R
Sowers
Rebecca
R
Rode
Wojciech
W
Pizzorno
Giuseppe
G
Cheng
Yung-Chi
YC
Kemeny
Nancy
N
Bertino
Joseph R
JR
Banerjee
Debabrata
D
D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C001943:5-fluorouridine; C023276:uridine monophosphate kinase; D009703:Nucleoside-Phosphate Kinase; D014529:Uridine