Eicosapentaenoic acid inhibits voltage-gated sodium channels and invasiveness in prostate cancer cells.
OBJECTIVE
The voltage-gated Na(+) channels (Na(v)) and their corresponding current (I(Na)) are involved in several cellular processes, crucial to metastasis of cancer cells. We investigated the effects of eicosapentaenoic (EPA), an omega-3 polyunsaturated fatty acid, on I(Na) and metastatic functions (cell proliferation, endocytosis and invasion) in human and rat prostate cancer cell lines (PC-3 and Mat-LyLu cells).


METHODS
The whole-cell voltage clamp technique and conventional/quantitative real-time reverse transcriptase polymerase chain reaction analysis were used. The presence of Na(v) proteins was shown by immunohistochemical methods. Alterations in the fatty acid composition of phospholipids after treatment with EPA and metastatic functions were also examined.


RESULTS
A transient inward Na(+) current (I(Na)), highly sensitive to tetrodotoxin, and Na(V) proteins were found in these cells. Expression of Na(V)1.6 and Na(V)1.7 transcripts (SCN8A and SCN9A) was predominant in PC-3 cells, while Na(V)1.7 transcript (SCN9A) was the major component in Mat-LyLu cells. Tetrodotoxin or synthetic small interfering RNA targeted for SCN8A and SCN9A inhibited metastatic functions (endocytosis and invasion), but failed to inhibit proliferation in PC-3 cells. Exposure to EPA produced a rapid and concentration-dependent suppression of I(Na). In cells chronically treated (up to 72h) with EPA, the EPA content of cell lipids increased time-dependently, while arachidonic acid content decreased. Treatment of PC-3 cells with EPA decreased levels of mRNA for SCN9A and SCN8A, cell proliferation, invasion and endocytosis.


CONCLUSIONS
Treatment with EPA inhibited I(Na) directly and also indirectly, by down-regulation of Na(v) mRNA expression in prostate cancer cells, thus inhibiting their metastatic potential.
Nakajima
T
T
Department of Ischemic Circulatory Physiology, The University of Tokyo, Japan. masamasa@pb4.so-net.ne.jp
Kubota
N
N
Tsutsumi
T
T
Oguri
A
A
Imuta
H
H
Jo
T
T
Oonuma
H
H
Soma
M
M
Meguro
K
K
Takano
H
H
Nagase
T
T
Nagata
T
T
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D009361:Neoplasm Invasiveness; D018408:Patch-Clamp Techniques; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D034741:RNA, Small Interfering; D015222:Sodium Channels; D015118:Eicosapentaenoic Acid