PMID- 29117941
OWN - NLM
STAT- MEDLINE
DCOM- 20190111
LR  - 20230325
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Linking)
VI  - 16
IP  - 2
DP  - 2018 Feb
TI  - Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient 
      Cells to 5-FdU.
PG  - 212-221
LID - 10.1158/1541-7786.MCR-17-0215 [doi]
AB  - Thymidylate synthase (TS) inhibitors including fluoropyrimidines [e.g., 
      5-Fluorouracil (5-FU) and 5-Fluorodeoxyuridine (5-FdU, floxuridine)] and 
      antifolates (e.g., pemetrexed) are widely used against solid tumors. Previously, 
      we reported that shRNA-mediated knockdown (KD) of uracil DNA glycosylase (UDG) 
      sensitized cancer cells to 5-FdU. Because p53 has also been shown as a critical 
      determinant of the sensitivity to TS inhibitors, we further interrogated 5-FdU 
      cytotoxicity after UDG depletion with regard to p53 status. By analyzing a panel 
      of human cancer cells with known p53 status, it was determined that p53-mutated 
      or -deficient cells are highly resistant to 5-FdU. UDG depletion resensitizes 
      5-FdU in p53-mutant and -deficient cells, whereas p53 wild-type (WT) cells are 
      not affected under similar conditions. Utilizing paired HCT116 p53 WT and p53 
      knockout (KO) cells, it was shown that loss of p53 improves cell survival after 
      5-FdU, and UDG depletion only significantly sensitizes p53 KO cells. This 
      sensitization can also be recapitulated by UDG depletion in cells with p53 KD by 
      shRNAs. In addition, sensitization is also observed with pemetrexed in p53 KO 
      cells, but not with 5-FU, most likely due to RNA incorporation. Importantly, in 
      p53 WT cells, the apoptosis pathway induced by 5-FdU is activated independent of 
      UDG status. However, in p53 KO cells, apoptosis is compromised in UDG-expressing 
      cells, but dramatically elevated in UDG-depleted cells. Collectively, these 
      results provide evidence that loss of UDG catalyzes significant cell death 
      signals only in cancer cells mutant or deficient in p53.Implications: This study 
      reveals that UDG depletion restores sensitivity to TS inhibitors and has 
      chemotherapeutic potential in the context of mutant or deficient p53. Mol Cancer 
      Res; 16(2); 212-21. (c)2017 AACR.
CI  - (c)2017 American Association for Cancer Research.
FAU - Yan, Yan
AU  - Yan Y
AD  - Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
FAU - Qing, Yulan
AU  - Qing Y
AD  - Case Comprehensive Cancer Center, Division of General Medical Sciences-Oncology, 
      Case Western Reserve University, Cleveland, Ohio.
FAU - Pink, John J
AU  - Pink JJ
AD  - Case Comprehensive Cancer Center, Division of General Medical Sciences-Oncology, 
      Case Western Reserve University, Cleveland, Ohio.
FAU - Gerson, Stanton L
AU  - Gerson SL
AD  - Case Comprehensive Cancer Center, Division of General Medical Sciences-Oncology, 
      Case Western Reserve University, Cleveland, Ohio. slg5@case.edu.
LA  - eng
GR  - P30 CA043703/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20171108
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 4494-26-2 (5-formyl-2'-deoxyuridine)
RN  - EC 3.2.2.- (Uracil-DNA Glycosidase)
RN  - W78I7AY22C (Deoxyuridine)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Deoxyuridine/*analogs & derivatives/pharmacology
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Drug Synergism
MH  - Gene Knockdown Techniques/methods
MH  - Gene Knockout Techniques
MH  - HCT116 Cells
MH  - Humans
MH  - *Mutation
MH  - Neoplasms/drug therapy/*genetics
MH  - Pemetrexed/pharmacology
MH  - RNA, Small Interfering/*pharmacology
MH  - Tumor Suppressor Protein p53/antagonists & inhibitors/*genetics
MH  - Uracil-DNA Glycosidase/*deficiency
EDAT- 2017/11/10 06:00
MHDA- 2019/01/12 06:00
CRDT- 2017/11/10 06:00
PHST- 2017/04/21 00:00 [received]
PHST- 2017/08/02 00:00 [revised]
PHST- 2017/10/26 00:00 [accepted]
PHST- 2017/11/10 06:00 [pubmed]
PHST- 2019/01/12 06:00 [medline]
PHST- 2017/11/10 06:00 [entrez]
AID - 1541-7786.MCR-17-0215 [pii]
AID - 10.1158/1541-7786.MCR-17-0215 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2018 Feb;16(2):212-221. doi: 10.1158/1541-7786.MCR-17-0215. Epub 
      2017 Nov 8.