PMID- 15937149
OWN - NLM
STAT- MEDLINE
DCOM- 20051021
LR  - 20131121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 314
IP  - 3
DP  - 2005 Sep
TI  - Proliferative signaling by store-operated calcium channels opposes colon cancer 
      cell cytostasis induced by bacterial enterotoxins.
PG  - 1013-22
AB  - Guanylyl cyclase C and accumulation of cGMP induced by bacterial heat-stable 
      enterotoxins (STs) promote colon cancer cell cytostasis, serving as a tumor 
      suppressor in intestine. Conversely, capacitative calcium entry through 
      store-operated calcium channels (SOCs) is a key signaling mechanism that promotes 
      colon cancer cell proliferation. The present study revealed that proliferative 
      signaling by capacitative calcium entry through SOCs opposes and is reciprocally 
      coupled to cytostasis mediated by guanylyl cyclase C in T84 human colon carcinoma 
      cells. Elimination of capacitative calcium entry employing 
      2-aminoethoxydiphenylborate (2-APB), a selective inhibitor of SOCs, potentiated 
      cytostasis induced by ST. Opposition of ST-induced cytostasis by capacitative 
      calcium entry reflects reciprocal inhibition of guanylyl cyclase C signaling. 
      Calcium entry through SOCs induced by the calcium-ATPase inhibitor thapsigargin 
      or the receptor agonists UTP or carbachol inhibited guanylyl cyclase C-dependent 
      cGMP accumulation. This effect was mimicked by the calcium ionophore ionomycin 
      and blocked by 2-APB and intracellular 
      1,2-bis(o-amino-5,5'-dibromophenoxy)ethane-N,N,N',N'-tetraacetic 
      acid-acetoxymethyl ester (BAPTA-AM), a chelator of calcium. Moreover, regulation 
      by capacitative calcium entry reflected ligand-dependent sensitization of 
      guanylyl cyclase C to inhibition by that cation. Although basal catalytic 
      activity was refractory, ST-stimulated guanylyl cyclase C was inhibited by 
      calcium, which antagonized binding of magnesium to allosteric sites required for 
      receptor-effector coupling. These observations demonstrate that reciprocal 
      regulation of guanylyl cyclase C signaling by capacitative calcium entry through 
      SOCs represents one limb of a coordinated mechanism balancing colon cancer cell 
      proliferation and cytostasis. They suggest that combining guanylyl cyclase C 
      agonists and SOC inhibitors offers a novel paradigm for cGMP-directed therapy and 
      prevention for colorectal tumors.
FAU - Kazerounian, Shiva
AU  - Kazerounian S
AD  - Division of Clinical Pharmacology, Department of Medicine, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Pitari, Giovanni M
AU  - Pitari GM
FAU - Shah, Fawad J
AU  - Shah FJ
FAU - Frick, Glen S
AU  - Frick GS
FAU - Madesh, Muniswamy
AU  - Madesh M
FAU - Ruiz-Stewart, Inez
AU  - Ruiz-Stewart I
FAU - Schulz, Stephanie
AU  - Schulz S
FAU - Hajnoczky, Gyorgy
AU  - Hajnoczky G
FAU - Waldman, Scott A
AU  - Waldman SA
LA  - eng
GR  - CA75123/CA/NCI NIH HHS/United States
GR  - CA79663/CA/NCI NIH HHS/United States
GR  - CA95026/CA/NCI NIH HHS/United States
GR  - GM59419/GM/NIGMS NIH HHS/United States
GR  - HL59214/HL/NHLBI NIH HHS/United States
GR  - HL59214-0151/HL/NHLBI NIH HHS/United States
GR  - K30 HL004522/HL/NHLBI NIH HHS/United States
GR  - T32 GM08562/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050603
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Bacterial Toxins)
RN  - 0 (Calcium Channels)
RN  - 0 (Enterotoxins)
RN  - 0 (Escherichia coli Proteins)
RN  - 0 (heat stable toxin (E coli))
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - H2D2X058MU (Cyclic GMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Bacterial Toxins/*pharmacology
MH  - Calcium/metabolism
MH  - Calcium Channels/*physiology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Colonic Neoplasms/drug therapy/*pathology
MH  - Cyclic GMP/physiology
MH  - Enterotoxins/*pharmacology
MH  - Escherichia coli Proteins
MH  - Guanylate Cyclase/physiology
MH  - Humans
MH  - Signal Transduction
EDAT- 2005/06/07 09:00
MHDA- 2005/10/22 09:00
CRDT- 2005/06/07 09:00
PHST- 2005/06/07 09:00 [pubmed]
PHST- 2005/10/22 09:00 [medline]
PHST- 2005/06/07 09:00 [entrez]
AID - jpet.105.089052 [pii]
AID - 10.1124/jpet.105.089052 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2005 Sep;314(3):1013-22. doi: 10.1124/jpet.105.089052. Epub 
      2005 Jun 3.