Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer

Wang, Shihua; Wan, Jin; Suburu, Janel; Gu, Zhennan; Cai, Jiaozhong; Axanova, Linara S.; Cramer, Scott D.; Thomas, Michael J.; Perry, Donna L.; Edwards, Iris J.; Mucci, Lorelei A.; Sinnott, Jennifer A.; Loda, Massimo; Sui, Guangchao; Berquin, Isabelle M.; Chen, Yong Q.

doi:10.1093/carcin/bgr290

Cited by 48 publications

(50 citation statements)

References 33 publications

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“…1B), PTEN +/+ cells formed smooth, rounded acini, whereas the PTEN −/− cells manifested as an invasive and nonpolarized morphotype. In agreement with a previous report (14), control PTEN −/− murine prostate epithelial cells were tumorigenic (Fig. 1C), whereas PTEN +/+ cells fail to grow in animals (data not shown).…”

Section: Resultssupporting

confidence: 93%

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A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

Christensen

Najy

Snyder

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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Purpose Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials PTEN wild-type (PTEN+/+) and PTEN knockout (PTEN−/−) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN−/− cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results PTEN−/− cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN−/− cells demonstrated increased clonogenic survival in vitro compared to PTEN+/+, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN−/− cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN−/− cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions We propose that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study.

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Section: Resultssupporting

confidence: 93%

“…Establishment and characterization of murine and PTEN −/− prostate cell lines has been described previously (12, 14). Briefly, the cells are spontaneously immortalized prostate cells obtained from wild-type PTEN mice, and matching littermates with a prostate-specific deletion of PTEN.…”

Section: Methodsmentioning

confidence: 99%

A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

Christensen

Najy

Snyder

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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“…The doses initially used for EPA and DHA were selected based on a literature survey; detailed dose-response data will be presented later. Notably, the doses used here are considerably lower than those used in previous studies with prostate cancer cells (Chung et al, 2001;Wang et al, 2012). Ethanol was used as a vehicle control for EPA/DHA, and BSA as a vehicle control for LPA; neither vehicle affected responses at the concentrations used (data not shown).…”

Section: Resultsmentioning

confidence: 88%

“…With respect to cancer prevention or therapy, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to suppress the growth of carcinoma cells in culture, including prostate cancer cells (Chung et al, 2001;Wang et al, 2012). Overexpression of FAT1, which converts n-6 to n-3 FAs, inhibits proliferation of DU145 and PC-3 prostate cancer cells (Lu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells

Liu

Hopkins

Quisenberry

et al. 2014

J Pharmacol Exp Ther

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Omega-3 fatty acids (n-3 FAs) are proposed to have many beneficial effects on human health. However, the mechanisms underlying their potential cancer preventative effects are unclear. G protein-coupled receptors (GPCRs) of the free fatty acid receptor (FFAR) family, FFA1/GPR40 and FFA4/GPR120, specifically bind n-3 FAs as agonist ligands. In this study, we examined the effects of n-3 FAs in human prostate cancer cell lines. Initial studies established that the long-chain n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid, inhibit proliferation of DU145 cells in response to lysophosphatidic acid (LPA), a mitogenic lipid mediator. When added alone to serumstarved DU145 cells, EPA transiently activates signaling events, including p70S6K phosphorylation. However, when added 15 minutes prior to LPA, EPA suppresses LPA-induced activating phosphorylations of ERK, FAK, and p70S6K, and expression of the matricellular protein CCN1. The rapid onset of the inhibitory action of EPA suggested involvement of a GPCR. Further studies showed that DU145 and PC-3 cells express mRNA and protein for both -2-yl)methoxy]-benzenepropanoic acid), a selective agonist for FFA4, exerts inhibitory effects on LPAand epidermal growth factor-induced proliferation and migration, similar to EPA, in DU145 and PC-3 cells. The effects of TUG-891 and EPA are readily reversible. The FFA1/FFA4 agonist GW9508 (4-[[(3-phenoxyphenyl)methyl]amino]-benzenepropranoic acid) likewise inhibits proliferation at doses that block FFA4. Knockdown of FFA4 expression prevents EPA-and TUG-891-induced inhibition of growth and migration. Together, these results indicate that activation of FFA4 initiates signaling events that can inhibit growth factor-induced signaling, providing a novel mechanism for suppression of cancer cell proliferation.

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“…These cells were maintained in RPMI1640 medium containing 5% FBS and 30 μg/mL of Hygromycin. Homozygous and heterozygous mouse prostate epithelial cells derived from mice harboring a specific deletion of phosphatase and tensin homologue (PTEN) in the mouse prostate epithelium (PTEN −/− and PTEN +/− , respectively) (33, 34) were cultured in DMEM supplemented with 5% FBS, L-glutamine and antibiotics (penicillin/streptomycin) (35). …”

Section: Methodsmentioning

confidence: 99%

Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity

et al. 2015

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Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of 2D, 3D and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that, depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres, displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, Docetaxel, MS275 and Salinomycin were all cytotoxic. In suspension, while MS275 and Salinomycin were toxic, Docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to Salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension, and to Salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity, and enhances tumor sensitivity to Salinomycin which may hold promise in overcoming tumor cell heterogeneity and plasticity.

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Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer

Cited by 48 publications

References 33 publications

A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells

Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity

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