PMID- 24563620
OWN - NLM
STAT- MEDLINE
DCOM- 20140909
LR  - 20211021
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 16
IP  - 1
DP  - 2014 Jan
TI  - Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and 
      GastrininAPCMin/+ intestinal polyposis model.
PG  - 73-83
AB  - Though long-term administration of proton pump inhibitor (PPI) imposed the risk 
      of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt 
      increases of colon cancer risk were witnessed after a long-term cohort study. Our 
      recent investigation revealed that PPI prevented colitis-associated 
      carcinogenesis through anti-inflammatory, anti-oxidative, and anti-mutagenic 
      mechanisms in spite of hypergastrinemia. Therefore, we hypothesized that PPI 
      might either antagonize the trophic action of gastrin on gastrointestinal 
      tumorigenesis or synergize to exert augmented anti-tumorigenic actions. We 
      challenged APCMin/+ mice with gastrin, PPI, PPI and gastrin together for 10 weeks 
      and counted intestinal polyposis accompanied with molecular changes. Gastrin 
      significantly increased intestinal polyposis, but combination of PPI and gastrin 
      markedly attenuated intestinal polyposis compared to gastrin-promoted APCMin/+ 
      mice (P<.001), in which significant beta-catenin phosphorylation and inhibition of 
      beta-catenin nuclear translocation were observed with PPI alone or combination of 
      PPI and gastrin, whereas gastrin treatment significantly increased beta-catenin 
      nuclear translocation. Significant footprints of apoptosis, G0/G1 accumulation, 
      inactivation of p38 and extracellular signal-regulated kinase, decreased 
      expressions of CD31, and inhibition of tumor necrosis factor-alpha and 
      cyclooxygenase-2 were noted in the combination group. In vitro investigations 
      were similar to in vivo findings as shown that PPI treatment inhibited the 
      binding of gastrin to its receptor, inactivated beta-catenin-associated signaling 
      including Tcf/Lef and glycogen synthase kinase beta, and paradoxically inhibited 
      beta-catenin-associated proliferative activities. Our investigations explain why 
      colon cancer risk has not increased despite long-term use of PPIs and provide a 
      rationale for using PPI to achieve anti-tumorigenesis beyond acid suppression.
FAU - Han, Young-Min
AU  - Han YM
AD  - CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, 
      Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
FAU - Hahm, Ki Baik
AU  - Hahm KB
AD  - CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, 
      Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
FAU - Park, Jong-Min
AU  - Park JM
AD  - CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, 
      Seoul, South Korea.
FAU - Hong, Sung Pyo
AU  - Hong SP
AD  - College of Pharmacy, CHA University, Pocheon, South Korea.
FAU - Kim, Eun-Hee
AU  - Kim EH
AD  - CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, 
      Seoul, South Korea ; College of Pharmacy, CHA University, Pocheon, South Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (2-Pyridinylmethylsulfinylbenzimidazoles)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CTNNB1 protein, mouse)
RN  - 0 (Gastrins)
RN  - 0 (Platelet Endothelial Cell Adhesion Molecule-1)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (beta Catenin)
RN  - D8TST4O562 (Pantoprazole)
RN  - EC 1.14.99.- (Ptgs2 protein, mouse)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
SB  - IM
MH  - 2-Pyridinylmethylsulfinylbenzimidazoles/chemistry
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Antineoplastic Agents/chemistry
MH  - Apoptosis
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Colonic Neoplasms/genetics
MH  - Cyclooxygenase 2/metabolism
MH  - Gastrins/*genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Inflammation
MH  - Intestinal Polyposis/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neoplasm Transplantation
MH  - Neoplasms, Experimental/*genetics
MH  - Pantoprazole
MH  - Platelet Endothelial Cell Adhesion Molecule-1/metabolism
MH  - Proton Pump Inhibitors/*chemistry
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - beta Catenin/metabolism
PMC - PMC3924549
EDAT- 2014/02/25 06:00
MHDA- 2014/09/10 06:00
PMCR- 2014/01/01
CRDT- 2014/02/25 06:00
PHST- 2013/08/21 00:00 [received]
PHST- 2013/12/03 00:00 [revised]
PHST- 2013/12/19 00:00 [accepted]
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2014/09/10 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - S1476-5586(14)80007-9 [pii]
AID - 131510 [pii]
AID - 10.1593/neo.131510 [doi]
PST - ppublish
SO  - Neoplasia. 2014 Jan;16(1):73-83. doi: 10.1593/neo.131510.