PMID- 32764831
OWN - NLM
STAT- MEDLINE
DCOM- 20200928
LR  - 20200928
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 8
DP  - 2020
TI  - CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I 
      degradation and irinotecan drug resistance in colorectal cancer.
PG  - e0228002
LID - 10.1371/journal.pone.0228002 [doi]
LID - e0228002
AB  - Irinotecan specifically targets topoisomerase I (topoI), and is used to treat 
      various solid tumors, but only 13-32% of patients respond to the therapy. Now, it 
      is understood that the rapid rate of topoI degradation in response to irinotecan 
      causes irinotecan resistance. We have published that the deregulated DNA-PKcs 
      kinase cascade ensures rapid degradation of topoI and is at the core of the drug 
      resistance mechanism of topoI inhibitors, including irinotecan. We also 
      identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary 
      upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports 
      showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. 
      The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 
      activity and its impact on irinotecan-based therapy in colon cancer. Using 
      differentially expressing CTDSP1 cells, we demonstrated that CTDSP1 contributes 
      to the irinotecan sensitivity by preventing topoI degradation. Retrospective 
      analysis of patients receiving irinotecan with or without rabeprazole has shown 
      the effects of CTDSP1 on irinotecan response. These results indicate that CTDSP1 
      promotes sensitivity to irinotecan and rabeprazole prevents this effect, 
      resulting in drug resistance. To ensure the best chance at effective treatment, 
      rabeprazole may not be a suitable PPI for cancer patients treated with 
      irinotecan.
FAU - Matsuoka, Hiroya
AU  - Matsuoka H
AUID- ORCID: 0000-0002-7733-7248
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Ando, Koji
AU  - Ando K
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Swayze, Emma J
AU  - Swayze EJ
AD  - Division of Hematology and Medical Oncology, Department of Medicine, Boston 
      University School of Medicine, Boston, Massachusetts, United States of America.
FAU - Unan, Elizabeth C
AU  - Unan EC
AD  - Division of Hematology and Medical Oncology, Department of Medicine, Boston 
      University School of Medicine, Boston, Massachusetts, United States of America.
FAU - Mathew, Joseph
AU  - Mathew J
AD  - Division of Hematology and Medical Oncology, Department of Medicine, Boston 
      University School of Medicine, Boston, Massachusetts, United States of America.
FAU - Hu, Quingjiang
AU  - Hu Q
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Tsuda, Yasuo
AU  - Tsuda Y
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Nakashima, Yuichiro
AU  - Nakashima Y
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Saeki, Hiroshi
AU  - Saeki H
AD  - Department of General Surgical Science, Graduate School of Medicine, Gunma 
      University, Maebashi, Gunma, Japan.
FAU - Oki, Eiji
AU  - Oki E
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
FAU - Bharti, Ajit K
AU  - Bharti AK
AD  - Division of Hematology and Medical Oncology, Department of Medicine, Boston 
      University School of Medicine, Boston, Massachusetts, United States of America.
FAU - Mori, Masaki
AU  - Mori M
AD  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka City, Fukuoka, Japan.
LA  - eng
PT  - Journal Article
DEP - 20200807
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Topoisomerase I Inhibitors)
RN  - 32828355LL (Rabeprazole)
RN  - 7673326042 (Irinotecan)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 3.1.3.16 (CTDSP1 protein, human)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 5.99.1.2 (DNA Topoisomerases, Type I)
RN  - EC 5.99.1.2 (TOP1 protein, human)
SB  - IM
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/metabolism
MH  - Colorectal Neoplasms/*metabolism/physiopathology
MH  - DNA
MH  - DNA Topoisomerases, Type I/*metabolism/physiology
MH  - DNA-Activated Protein Kinase/metabolism
MH  - Drug Resistance/drug effects
MH  - Drug Resistance, Neoplasm/physiology
MH  - Humans
MH  - Irinotecan/metabolism/pharmacology
MH  - Phosphoprotein Phosphatases/antagonists & inhibitors/metabolism
MH  - Proton Pump Inhibitors/pharmacology
MH  - Rabeprazole/*metabolism/pharmacology
MH  - Retrospective Studies
MH  - Topoisomerase I Inhibitors/pharmacology
PMC - PMC7413750
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/08/09 06:00
MHDA- 2020/09/29 06:00
PMCR- 2020/08/07
CRDT- 2020/08/09 06:00
PHST- 2020/01/04 00:00 [received]
PHST- 2020/06/30 00:00 [accepted]
PHST- 2020/08/09 06:00 [entrez]
PHST- 2020/08/09 06:00 [pubmed]
PHST- 2020/09/29 06:00 [medline]
PHST- 2020/08/07 00:00 [pmc-release]
AID - PONE-D-20-00259 [pii]
AID - 10.1371/journal.pone.0228002 [doi]
PST - epublish
SO  - PLoS One. 2020 Aug 7;15(8):e0228002. doi: 10.1371/journal.pone.0228002. 
      eCollection 2020.