Effects of Dietary Omega-3 Fatty Acids on Akt Signaling in Prostate Cancer

Summary

Principal Investigator: Yong Q Chen
Abstract: DESCRIPTION (provided by applicant): There are two major dietary sources of ?3 polyunsaturated fatty acid (PUFA): the botanic ?3 PUFA [1-linolenic acid (1LNA, 18:3n-3)] and the marine I3 PUFA [eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3)]. We have previously demonstrated that prostate cancer risk can be favorably modified by marine I3 PUFA in a genetically predisposed mouse population and that modulation of prostate cancer development by PUFA is mediated in part through Bad-dependent apoptosis. Our recent evidence shows that active Akt protein localizes on the plasma membrane in prostate tumor tissues from mice on I6 diet, whereas it is primarily localized in the cytoplasm in tumor tissues from mice on ?3 diet enriched with DHA. It is unclear how ?3 fatty acids alter Akt localization, and how this in turn affects the function of Akt substrates such as the proapoptotic Bad protein. In mammals, the first carbon (sn-1 position) of the glycerol backbone in phosphatidylinositols (PIP) is usually linked to a saturated fatty acid, the second carbon (sn-2 position) to an ? 6 PUFA, and the last carbon to inositol. We found that DHA can replace the ?6 fatty acid at the sn-2 position of PIPs in cell culture, thereby generating different species of PIPs. We hypothesize that ?6- and ? 3-containing PIPs will localize to different cellular membranes due to their differences in number and/or position of double bonds, resulting in Akt recruitment and activation at different cellular locations, and consequently differential Bad phosphorylation, apoptosis and tumor suppression. To test our hypothesis, we propose to (1) Determine if different I3 fatty acids are similarly incorporated on the sn-2 position of PIPs and if this incorporation affects their subcellular localization in vitro, (2) Determine if ?3 fatty acid incorporation affects the localization and activity of Akt and Bad in vitro, and (3) Confirm the ability of different I3 fatty acids to alter PIP and Akt localization as well as Bad phosphorylation and to suppress prostate cancer in vivo. PUBLIC HEALTH RELEVANCE: The PI3K/Pten/Akt pathway plays a critical role in human cancers. A large body of literature has illustrated the importance of phosphorylation on the inositol ring of phosphatidylinositols (PIP) in PI3K/Pten/Akt signaling. However, there is a complete lack of understanding of the possible role of fatty acids in PIP localization and function. Our preliminary results led us to hypothesize that, in cells or animals fed with ?3 polyunsaturated fatty acid (PUFA), ?3 fatty acids replace ?6 PUFA at the sn-2 position, thereby generating different species of PIPs with different biological functions. If our hypothesis is correct, the successful completion of the proposed work will demonstrate, for the first time, the role of dietary fatty acids in regulating PIP formation and Akt function.
Funding Period: 2004-07-08 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids
    Isabelle M Berquin
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    J Clin Invest 117:1866-75. 2007
  2. pmc PTEN regulates PDGF ligand switch for β-PDGFR signaling in prostate cancer
    M Katie Conley-LaComb
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Am J Pathol 180:1017-27. 2012
  3. pmc n-3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation
    Tim Y Hou
    Department of Biochemistry and Biophysics, Texas A and M University, College Station, Texas, USA
    Biochem J 443:27-37. 2012
  4. pmc Lipids and prostate cancer
    Janel Suburu
    Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
    Prostaglandins Other Lipid Mediat 98:1-10. 2012
  5. pmc Expression and purification of integral membrane fatty acid desaturases
    Haiqin Chen
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, People s Republic of China
    PLoS ONE 8:e58139. 2013
  6. pmc Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells
    Zhennan Gu
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China and
    Carcinogenesis 34:1968-75. 2013
  7. pmc ω3 fatty acid desaturases from microorganisms: structure, function, evolution, and biotechnological use
    Mingxuan Wang
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People s Republic of China
    Appl Microbiol Biotechnol 97:10255-62. 2013
  8. pmc Genome characterization of the oleaginous fungus Mortierella alpina
    Lei Wang
    TEDA School of Biological Sciences and Biotechnology, Nankai University, Tianjin Economic Technological Development Area, Tianjin, People s Republic of China
    PLoS ONE 6:e28319. 2011
  9. pmc Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer
    Shihua Wang
    Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA
    Carcinogenesis 33:404-12. 2012
  10. pmc Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway
    Haiguo Sun
    Department of Pathology, Wake ForestUniversity School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 32:1518-24. 2011

Detail Information

Publications21

  1. pmc Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids
    Isabelle M Berquin
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    J Clin Invest 117:1866-75. 2007
    ..Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer...
  2. pmc PTEN regulates PDGF ligand switch for β-PDGFR signaling in prostate cancer
    M Katie Conley-LaComb
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Am J Pathol 180:1017-27. 2012
    ..Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/β-PDGFR signal transduction...
  3. pmc n-3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation
    Tim Y Hou
    Department of Biochemistry and Biophysics, Texas A and M University, College Station, Texas, USA
    Biochem J 443:27-37. 2012
    ..Collectively, these data demonstrate that n-3 PUFA, such as DHA, alter PtdIns(4,5)P2 in CD4+ T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4+ T-cells...
  4. pmc Lipids and prostate cancer
    Janel Suburu
    Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
    Prostaglandins Other Lipid Mediat 98:1-10. 2012
    ..Here, we highlight the lipogenic nature of prostate cancer, especially the promotion of de novo lipid synthesis, and the significance of various dietary lipids in prostate cancer development and progression...
  5. pmc Expression and purification of integral membrane fatty acid desaturases
    Haiqin Chen
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, People s Republic of China
    PLoS ONE 8:e58139. 2013
    ..7% (Ca. 37.5 mg/L of culture) for FADS9-I. Successful expression of high amounts of recombinant proteins represents a critical step towards the structural elucidation of membrane fatty acid desaturases...
  6. pmc Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells
    Zhennan Gu
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China and
    Carcinogenesis 34:1968-75. 2013
    ..Our study highlights a potential novel mechanism of cancer inhibition by ω3 PUFA through alteration of PIP3 and AKT localization and affecting the AKT signaling pathway...
  7. pmc ω3 fatty acid desaturases from microorganisms: structure, function, evolution, and biotechnological use
    Mingxuan Wang
    State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People s Republic of China
    Appl Microbiol Biotechnol 97:10255-62. 2013
    ....
  8. pmc Genome characterization of the oleaginous fungus Mortierella alpina
    Lei Wang
    TEDA School of Biological Sciences and Biotechnology, Nankai University, Tianjin Economic Technological Development Area, Tianjin, People s Republic of China
    PLoS ONE 6:e28319. 2011
    ..Our study provides the first draft genome and comprehensive lipid profile for M. alpina, and lays the foundation for possible genetic engineering of M. alpina to produce higher levels and diverse contents of dietary lipids...
  9. pmc Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer
    Shihua Wang
    Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA
    Carcinogenesis 33:404-12. 2012
    ..Dietary omega-3 PUFA supplementation in conjunction with androgen ablation may significantly delay the development of castration-resistant prostate cancer in patients compared with androgen ablation alone...
  10. pmc Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway
    Haiguo Sun
    Department of Pathology, Wake ForestUniversity School of Medicine, Winston Salem, NC 27157, USA
    Carcinogenesis 32:1518-24. 2011
    ..These data elucidate a pathway whereby SDC-1, upregulated by DHA, induces apoptosis in breast cancer cells through inhibition of MEK/Erk/Bad signaling...
  11. ncbi Dietary fat-gene interactions in cancer
    Yong Q Chen
    Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA
    Cancer Metastasis Rev 26:535-51. 2007
    ..The purpose of this review is to present a more cohesive view of dietary fat-gene interactions, and outline a working hypothesis of the intricate connection between fat, genes and cancer...
  12. pmc Membrane targeting by APPL1 and APPL2: dynamic scaffolds that oligomerize and bind phosphoinositides
    HEIDI J CHIAL
    Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA
    Traffic 9:215-29. 2008
    ....
  13. pmc In vivo and in vitro regulation of syndecan 1 in prostate cells by n-3 polyunsaturated fatty acids
    Iris J Edwards
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
    J Biol Chem 283:18441-9. 2008
    ..These findings indicate that syndecan 1 is up-regulated by n-3 fatty acids by a transcriptional pathway involving PPARgamma. This mechanism may contribute to the chemopreventive properties of n-3 fatty acids in prostate cancer...
  14. pmc Multi-targeted therapy of cancer by omega-3 fatty acids
    Isabelle M Berquin
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, United States
    Cancer Lett 269:363-77. 2008
    ..In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials...
  15. pmc Posttranslational regulation of membrane type 1-matrix metalloproteinase (MT1-MMP) in mouse PTEN null prostate cancer cells: Enhanced surface expression and differential O-glycosylation of MT1-MMP
    Seaho Kim
    Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
    Biochim Biophys Acta 1803:1287-97. 2010
    ....
  16. pmc APPL proteins FRET at the BAR: direct observation of APPL1 and APPL2 BAR domain-mediated interactions on cell membranes using FRET microscopy
    HEIDI J CHIAL
    Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 5:e12471. 2010
    ..Although previous studies have shown that APPL minimal BAR domains associate with curved cell membranes, direct interaction between APPL BAR domains on cell membranes in vivo has not been reported...
  17. pmc Syndecan-1-dependent suppression of PDK1/Akt/bad signaling by docosahexaenoic acid induces apoptosis in prostate cancer
    Yunping Hu
    Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC, USA
    Neoplasia 12:826-36. 2010
    ..The effect of DHA on PDK1/Akt/Bad signaling was abrogated by SDC-1 siRNA. These findings define a mechanism by which SDC-1-dependent suppression of phosphorylation of PDK1/Akt/Bad mediates n-3 PUFA-induced apoptosis in prostate cancer...
  18. pmc Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-1
    Haiguo Sun
    Department of Pathology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
    PLoS ONE 6:e20502. 2011
    ..This was accompanied by higher SDC-1 in mammary glands and livers of Fat-1 mice, thus demonstrating that endogenously synthesized n-3 PUFA may upregulate SDC-1 in the presence of high dietary n-6 PUFA...
  19. pmc Fatty acid synthase is required for mammary gland development and milk production during lactation
    Janel Suburu
    Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, North Carolina
    Am J Physiol Endocrinol Metab 306:E1132-43. 2014
    ..These results demonstrate that FASN is essential for the development, functional competence, and maintenance of the lactating mammary gland. ..