Fish oil targets PTEN to regulate NFκB for downregulation of anti-apoptotic genes in breast tumor growth

Abstract

The molecular mechanism for the beneficial effect of fish oil on breast tumor growth is largely undefined. Using the xenograft model in nude mice, we for the first time report that the fish oil diet significantly increased the level of PTEN protein in the breast tumors. In addition, the fish oil diet attenuated the PI 3 kinase and Akt kinase activity in the tumors leading to significant inhibition of NFκB activation. Fish oil diet also prevented the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL in the breast tumors with concomitant increase in caspase 3 activity. To extend these findings we tested the functional effects of DHA and EPA, the two active ω-3 fatty acids of fish oil, on cultured MDA MB-231 cells. In agreement with our in vivo data, DHA and EPA treatment increased PTEN mRNA and protein expression and inhibited the phosphorylation of p65 subunit of NFκB in MDA MB-231 cells. Furthermore, DHA and EPA reduced expression of Bcl-2 and Bcl-XL. NFκB DNA binding activity and NFκB-dependent transcription of Bcl-2 and Bcl-XL genes were also prevented by DHA and EPA treatment. Finally, we showed that PTEN expression significantly inhibited NFκB-dependent transcription of Bcl-2 and Bcl-XL genes. Taken together, our data reveals a novel signaling pathway linking the fish oil diet to increased PTEN expression that attenuates the growth promoting signals and augments the apoptotic signals, resulting in breast tumor regression.

Peroxisome Proliferator- Activated Receptor-gamma and Nuclear Factor-kappa B in Obese Breast Cancer Patients: Correlation with Omega-3 polyunsaturated Fatty Acids with Adjuvant Chemotherapy

“…(65) Also, it was documented that dietary fish oil significantly suppressed the phospho-inositol 3 kinase (PI3 kinase) activity in the breast tumor, resulting in reduced Akt kinase and NF-κB p65 subunit phosphorylation and anti-apoptotic protein expression. In addition, Ghosh-Choudhury T et al (66), showed that the active constituents of fish oil, DHA and EPA, inhibit NF-κB transcriptional activation, resulting in attenuation of the antiapoptotic gene transcription which confirms our results of decreased NF-κB by omega-3 adjuvant treatment.…”

Simvastatin Prevents Skeletal Metastasis of Breast Cancer by an Antagonistic Interplay between p53 and CD44

“…Preparation of Cell and Tumor Lysates-Excised tumors were homogenized as described previously (10,24). Briefly, the tumors were lysed in RIPA buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 0.05% aprotinin, and 1% Nonidet P-40).…”

“…Transfection and Luciferase Activity-MDA-MB-231 mammary cancer cells were transfected with the indicated expression vectors and luciferase reporter constructs using FuGENE HD as described previously (24,26,27). Cell lysates were used for immunoblotting or luciferase assay as described previously using the luciferase assay kit (24,26,27).…”

Efeitos do ácido docosahexaenoico (DHA) e do ácido araquidônico (AA) sobre a morte celular da linhagem celular de câncer de mama MDA-MB-231

“…No presente estudo não foi verificada a translocação dessa proteína após estímulo com DHA por 18 horas. Pesquisas mostram que o DHA e o EPA diminuem significativamente a ligação de NFkB ao DNA em células MDA-MB-231 (45,46), corroborando com os nossos achados. Além disso, Horia e colaboradores (47) mostraram que o DHA é capaz de diminuir a expressão gênica de NFkB em MDA-MB- inicia-se a partir de 6 horas de tratamento e estende-se até 24 horas.…”