Voltage-gated Sodium Channel Activity Promotes Cysteine Cathepsin-dependent Invasiveness and Colony Growth of Human Cancer Cells.
Voltage-gated sodium channels (Na(V)) are functionally expressed in highly metastatic cancer cells derived from nonexcitable epithelial tissues (breast, prostate, lung, and cervix). MDA-MB-231 breast cancer cells express functional sodium channel complexes, consisting of Na(V)1.5 and associated auxiliary beta-subunits, that are responsible for a sustained inward sodium current at the membrane potential. Although these channels do not regulate cellular multiplication or migration, their inhibition by the specific blocker tetrodotoxin impairs both the extracellular gelatinolytic activity (monitored with DQ-gelatin) and cell invasiveness leading to the attenuation of colony growth and cell spreading in three-dimensional Matrigel-composed matrices. MDA-MB-231 cells express functional cysteine cathepsins, which we found play a predominant role ( approximately 65%) in cancer invasiveness. Matrigel invasion is significantly decreased in the presence of specific inhibitors of cathepsins B and S (CA-074 and Z-FL-COCHO, respectively), and co-application of tetrodotoxin does not further reduce cell invasion. This suggests that cathepsins B and S are involved in invasiveness and that their proteolytic activity partly depends on Na(V) function. Inhibiting Na(V) has no consequence for cathepsins at the transcription, translation, and secretion levels. However, Na(V) activity leads to an intracellular alkalinization and a perimembrane acidification favorable for the extracellular activity of these acidic proteases. We propose that Na(v) enhance the invasiveness of cancer cells by favoring the pH-dependent activity of cysteine cathepsins. This general mechanism could lead to the identification of new targets allowing the therapeutic prevention of metastases.
Gillet
Ludovic
L
INSERM U921, Nutrition, Croissance et Cancer, and INSERM U618, Protéases et Vectorisation Pulmonaires, Université François Rabelais, FacultédeMédecine, 37032 Tours, France.
Roger
Sébastien
S
Besson
Pierre
P
Lecaille
Fabien
F
Gore
Jacques
J
Bougnoux
Philippe
P
Lalmanach
Gilles
G
Le Guennec
Jean-Yves
JY
D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport / Q000187:drug effects; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009363:Neoplasm Proteins; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D013779:Tetrodotoxin; D012964:Sodium; D002403:Cathepsins; C533912:CTSB protein, human; D002401:Cathepsin B; C028217:cathepsin S