Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

Abstract

Different agents able to modulate apoptosis have been shown to modify the expression of the MAP-kinase-phosphatase-1 (MKP-1). The expression of this phosphatase has been considered a potential positive prognostic factor in lung cancer, and smoke was shown to reduce the levels of MKP-1 in ferret lung. Our aim was to assess whether the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), known to inhibit the growth of several cancer cells mainly inducing apoptosis, may exert pro-apoptotic effect in lung cancer cells by modifying MKP-1 expression. We observed that DHA increased MKP-1 protein and mRNA expression and induced apoptosis in different lung cancer cell lines (mink Mv1Lu adenocarcinoma cells, human A549 adenocarcinoma and human BEN squamous carcinoma cells). We inhibited the pro-apoptotic effect of DHA by treating the cells with the phosphatase inhibitor Na(3)VO(4) or by silencing the MKP-1 gene with the specific siRNA. This finding demonstrated that the induction of apoptosis by DHA involved a phosphatase activity, specifically that of MKP-1. DHA reduced also the levels of the phosphorylated MAP-kinases, especially ERK1/2 and p38. Such an effect was not observed when the MKP-1 gene was silenced. Altogether, the data provide evidence that the DHA-induced overexpression of MKP-1 and the resulting decrease of MAP-kinase phosphorylation by DHA may underlie the pro-apoptotic effect of this fatty acid in lung cancer cells. Moreover, they support the hypothesis that DHA may exert chemopreventive action in lung cancer.

Docosahexaenoic acid inhibits the phosphorylation of STAT3 and the growth and invasion of renal cancer cells

“…Increased consumption of omega-3 FAs has been associated with a lower incidence of various types of cancer, including colon (2), breast (3,4) and prostate cancer (3,4). It has also been demonstrated that omega-3 FAs exert a range of anti-tumor effects, including inhibitory effects on angiogenic mediator production (5), the induction of apoptosis (6), inhibitory effects on tumor invasion and metastasis (7,8) and regulatory effects on signaling pathways (9). In particular, the anti-tumor effects of EPA and DHA have been observed in breast cancer, whereby higher intakes of these FAs are associated with a reduced risk of mortality (10,11).…”

“…Cells at a density of 2x10 6 were treated with 0 (control), 50 and 100 µM DHA for 6 h, then lysed in radioimmunoprecipitation assay buffer composed of 10 mM tris-HCl (Nacalai Tesque, Inc., Kyoto, Japan), 150 mM NaCl (Kanto Chemical, Co., Inc., Tokyo, Japan), 1% Triton X-100 (MP Biomedicals LLC, Santa Ana, CA, USA), 5 µM ethylenediaminetetra acetic acid (Nacalai Tesque, Inc.), 1%sodium deoxycholate (Difco; BD Biosciences, San Jose, CA, USA), 0.1% sodium dodecyl sulfate, 1.2% aprotinin, 5 µM leupeptin, 4 µM antipain, 1 mM phenylmethylsulfonyl fluoride and 0.1 mM Na 3 VO 4 (all; Sigma Aldrich; Merck KGaA, Darmstadt, Germany) according to a previously described method (21). Samples were centrifuged at 16,000 x g for 20 min at 4˚C.…”

Time-resolved gene expression profiling of human squamous cell carcinoma cells during the apoptosis process induced by photodynamic treatment with hypericin

“…or p38 MAPK pathways being a negative regulator of ERK1/2, JNK or p38 MAPK , respectively. DUSP1 may induce apoptosis (27)(28)(29)(30). Following exposure to stress agents various degrees of histone H3 modification at the DUSP1 chromatin occurs.…”

The influence of selected nutritional components in lung cancer risk – unsaturated fatty acids, isothiocyanates, selenium

“…Jego działanie proapoptotyczne wynika m.in. z hamowania ekspresji enzymu cyklooksygenazy 2 (COX-2), powodującego wzrost guza oraz neoangiogenezę [15]. W badaniach Serini i wsp.…”

“…W badaniach Serini i wsp. [15] przeprowadzonych na liniach komórkowych: A549 -ludzkiego gruczolakoraka płuc, BEN -ludzkiego raka nabłonka płaskiego płuc, a także na linii komórek zwierzęcych Mv1Lu zaobserwowano indukcję apoptozy podczas 48-godzinnej inkubacji z DHA we wszystkich trzech liniach komórkowych. Stwierdzono, że 50-mikromolowy roztwór DHA spowodował ekspresję białka fosfatazy 1 dla kinazy białkowej aktywowanej mitogennie (MKP-1) w badanych liniach komórkowych.…”