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

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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.

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Abbreviations

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

PI:

Phosphatidylinositol

PH:

Pleckstrin homology

EMSA:

Electrophoretic mobility shift assay

LUC:

Luciferase

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Acknowledgments

This work was supported by the NIH RO1 AR52425, DOD Breast cancer Concept Award, Morrison Trust Fund and VA Merit Review grants to NGC. GGC is supported by NIH RO1 DK 50190, VA Merit Review and Juvenile Diabetes Research Foundation Regular Research Grants. GGC is recipient of the Research Career Scientist Award from the Department of Veterans Affairs. GF is supported by NIH RO1 AG023648.

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  1. Triparna Ghosh-Choudhury

    Present address: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Authors and Affiliations

  1. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Triparna Ghosh-Choudhury, Chandi C. Mandal, Kathleen Woodruff, Patricia St Clair & Nandini Ghosh-Choudhury

  2. Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Gabriel Fernandes & Goutam G. Choudhury

  3. Geriatric Research, Education and Clinical Center, San Antonio, TX, USA

    Goutam G. Choudhury

  4. South Texas Veterans Health Care System, San Antonio, TX, USA

    Goutam G. Choudhury & Nandini Ghosh-Choudhury

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Ghosh-Choudhury, T., Mandal, C.C., Woodruff, K. et al. Fish oil targets PTEN to regulate NFκB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res Treat 118, 213–228 (2009). https://doi.org/10.1007/s10549-008-0227-7

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