Eicosapentaenoic acid inhibits voltage‐gated sodium channels and invasiveness in prostate cancer cells

Abstract

Background and purpose:The voltage-gated Na + channels (Nav) and their corresponding current (INa) 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 INa and metastatic functions (cell proliferation, endocytosis and invasion) in human and rat prostate cancer cell lines (PC-3 and Mat-LyLu cells). Experimental approach: The whole-cell voltage clamp technique and conventional/quantitative real-time reverse transcriptase polymerase chain reaction analysis were used. The presence of Nav proteins was shown by immunohistochemical methods. Alterations in the fatty acid composition of phospholipids after treatment with EPA and metastatic functions were also examined. Key results: A transient inward Na + current (INa), highly sensitive to tetrodotoxin, and NaV proteins were found in these cells. Expression of NaV1.6 and NaV1.7 transcripts (SCN8A and SCN9A) was predominant in PC-3 cells, while NaV1.7 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 INa. 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. Conclusion and implications: Treatment with EPA inhibited INa directly and also indirectly, by down-regulation of Nav mRNA expression in prostate cancer cells, thus inhibiting their metastatic potential.

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

“…5E). Like NSCLC, metastatic prostate cancer is also associated with functional expression of Na v 1.7 (Diss et al, 2001;Diss et al, 2005;Nakajima et al, 2009;Yildirim et al, 2012). Together, these data support a role for Na v 1.7 in the development of an invasive cancer phenotype in vivo.…”

“…Voltage-gated Na + channels (Na v ), normally associated with cellular excitability, have been found to play crucial roles in metastatic behaviours of several cancers, including breast Fraser et al, 2005;Gao et al, 2009;Gillet et al, 2009;Roger et al, 2003), prostate (Abdul and Hoosein, 2002;Bennett et al, 2004;Diss et al, 2001;Diss et al, 2005;Grimes et al, 1995;Laniado et al, 1997;Nakajima et al, 2009;Smith et al, 1998), cervical (Diaz et al, 2007), colon (House et al, 2010), ovarian (Gao et al, 2010), SCLC (Blandino et al, 1995;Onganer and Djamgoz, 2005;Onganer et al, 2005;Pancrazio et al, 1989) and NSCLC (Roger et al, 2007). In prostate cancer, functional expression of Na v enhances cellular migration, invasion and endocytosis (Ding et al, 2008;UysalOnganer and Djamgoz, 2007).…”

Inhibition of PC3 human prostate cancer cell proliferation, invasion and migration by eicosapentaenoic acid and docosahexaenoic acid

“…It was also reported that LNCaP cell growth was inhibited by EPA and DHA (8). The effect of EPA and DHA on the proliferation and invasion of the breast cancer cell lines MDA-MB-231 and MDA-231 Luc and the effect of EPA and DHA on breast cancer metastasis to bone following intracardiac injection of MDA-MB-231 and MDA-231-Luc cells was also evaluated in other studies (9,10). In brief, MDA-MB-231 cells were injected into mice that were fed experimental diets containing EPA or DHA.…”

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…Several studies have shown that functional VGSC expression occurs in a variety of carcinomas and promotes metastatic behaviour. Such carcinomas include BCa as well as cancers of the prostate (Grimes et al 1995;Laniado et al 1997;Nakajima et al 2009), lung (Onganer and Djamgoz 2005;Campbell et al 2013), colon (House et al 2010) and cervix (Diaz et al 2007). It has been suggested, therefore, (1) that VGSC up-regulation is an early event in metastatic progression and (2) that VGSC expression is a 'switch,' necessary and sufficient for engaging cancer cells in a highly invasive state.…”