SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline.
BACKGROUND
Barely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells.


RESULTS
In the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action.


CONCLUSIONS
This study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.
INSERM UMR 1069, Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Maxime
M
Guéguinou
Equipe ERL 7368, CNRS, Université de Poitiers, Poitiers, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Thomas
T
Harnois
Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
David
D
Crottes
INSERM-UMR 1078 Université de Brest, Brest, France.|CHRU Brest, Service d'Anatomie et Cytologie Pathologiques, Brest, France.
Arnaud
A
Uguen
Equipe ERL 7368, CNRS, Université de Poitiers, Poitiers, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Nadine
N
Deliot
INSERM UMR 1069, Université de Tours, Tours, France.
Audrey
A
Gambade
INSERM UMR 1069, Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Aurélie
A
Chantôme
CNRS-UMR 6521-Université de Brest, Brest, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Jean Pierre
JP
Haelters
CNRS-UMR 6521-Université de Brest, Brest, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Paul Alain
PA
Jaffrès
INSERM UMR 1069, Université de Tours, Tours, France.|CHRU Tours, Tours, France.
Marie Lise
ML
Jourdan
INSERM UMR 1069, Université de Tours, Tours, France.
Günther
G
Weber
CNRS UMR 7299, INSERM-UMR 1099, Université de Nice Sophia-Antipolis, Nice, France.
Olivier
O
Soriani
INSERM UMR 1069, Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.|CHRU Tours, Tours, France.
Philippe
P
Bougnoux
INSERM-UMR 1078 Université de Brest, Brest, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Olivier
O
Mignen
Equipe ERL 7368, CNRS, Université de Poitiers, Poitiers, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Nicolas
N
Bourmeyster
Equipe ERL 7368, CNRS, Université de Poitiers, Poitiers, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Bruno
B
Constantin
GICC-UMR 7292 Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.|CHRU Tours, Tours, France.
Thierry
T
Lecomte
INSERM UMR 1069, Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Christophe
C
Vandier
INSERM UMR 1069, Université de Tours, Tours, France.|Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France.
Marie
M
Potier-Cartereau
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D006017:Glycolipids / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D021962:Membrane Microdomains / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D000071740:ORAI1 Protein / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*
C574297:1-O-hexadecyl-2-O-methylglycero-3-lactose; D000911:Antibodies, Monoclonal; D006017:Glycolipids; C406328:KCNN3 protein, human; D046912:Multiprotein Complexes; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium
Akt signaling; Ohmline; SOCE; anti-EGFR mAbs; lipid-raft channel complex