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Molecular Cancer Therapeutics
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Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice

Vanessa Fritz, Zohra Benfodda, Geneviève Rodier, Corinne Henriquet, François Iborra, Christophe Avancès, Yves Allory, Alexandre de la Taille, Stéphane Culine, Hubert Blancou, Jean Paul Cristol, Françoise Michel, Claude Sardet and Lluis Fajas
Vanessa Fritz
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Zohra Benfodda
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Geneviève Rodier
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Corinne Henriquet
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François Iborra
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Christophe Avancès
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Yves Allory
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Alexandre de la Taille
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Stéphane Culine
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Hubert Blancou
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Jean Paul Cristol
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Françoise Michel
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Claude Sardet
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Lluis Fajas
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DOI: 10.1158/1535-7163.MCT-09-1064 Published June 2010
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    Figure 1.

    MUFA content and SCD1 expression are increased with prostate cancer progression. The global desaturation index, which corresponds to the ratio of total MUFA to SFAs (A), and the specific desaturation indexes 16:1n-7/16:0 (B) and 18:1n-9/18:0 (C) in cholesterol esters (CE), triacylglycerides (TAG), and phospholipids (PL) are increased in prostate cancer tissue with Gleason score ≥7. Columns, mean; bars, SD. Human SCD1 is overexpressed in prostate cancer tissue with Gleason score ≥7 at mRNA (D) and protein (E) levels. F, the level of SCD1 expression was compared by immunofluorescence in PNT2 benign prostate cell line and in LNCaP and C4-2 tumoral prostate cell lines. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 2.

    Inhibition of SCD1 activity induces growth arrest of prostate cancer cells in vitro. A to D, autoradiography of TLC showing quantification of SCD1 Δ9-desaturase activity on LNCaP (A), C4-2 (B), and PNT2 (C) cells by measuring the conversion of exogenous 14C-saturated palmitic acid substrate into monounsaturated palmitoleic acid in control or 25 μmol/L BZ36–treated cells. D, SCD1 desaturase activity was expressed as the ratio of palmitoleic acid to palmitic acid after normalization to cellular DNA content. E to G, proliferation of tumoral LNCaP (E), C4-2 (F), and benign PNT2 (G) cells was measured with a hematocytometer at 24, 48, and 72 h following culture with increasing doses of BZ36. H, SCD1 immunoblot in LNCaP and C4-2 cell lines 24 and 48 h after transfection with control or siRNA against hSCD1. I and J, proliferation of LNCaP (I) and C4-2 (J) cells was measured by counting the percentage of BrdUrd incorporation at 24 and 48 h after siRNA transfection. Columns, mean of at least two independent experiments done in triplicates; bars, SD. *, P < 0.05; ***, P < 0.001.

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    Figure 3.

    Inhibition of SCD1 activity abrogates de novo FA synthesis in prostate cancer cells in vitro. A to C, [14C]palmitate incorporation into cholesterol ester, triacylglyceride, and phospholipid was measured in LNCaP (A), C4-2 (B), and PNT2 (C) cells after exposure to control media or 25 μmol/L BZ36. D to F, [14C]stearate incorporation into cholesterol ester, triacylglyceride, and phospholipid was measured in LNCaP (D), C4-2 (E), and PNT2 (F) cells after exposure to control medium or 25 μmol/L BZ36 inhibitor. Columns, mean of at least two independent experiments done in triplicates; bars, SD. *, P < 0.05; **, P < 0.01.

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    Figure 4.

    Inhibition of SCD1 activity decreases AKT/PI(3,4,5)P3 and GSK3α/β/β-catenin signaling pathways in prostate cancer cells in vitro. A and B, proteome analysis of the change in the phosphorylation status of indicated kinases in LNCaP (A) and C4-2 (B) cells 24 h after culture with 25 μmol/L BZ36 inhibitor. Level of phosphorylation was quantified using ImageJ software. Values are represented as relative fold change of phosphorylation level in cells treated with 25 μmol/L BZ36 inhibitor compared with cells cultured in control medium. Increase and decrease in phosphorylation level are indicated in red and blue, respectively. Columns, mean; bars, SD. MEK, MAPK/ERK kinase. C, immunoblot analysis of phospho-AKT, total AKT, phospho-AMPK, and total AMPK in LNCaP and C4-2 cells at 24 h following exposure to control media, 25 μmol/L BZ36 inhibitor, or 1 mmol/L AICAR. D, immunoblot analysis of phospho-ERK1/2, total ERK1/2, phospho-GSK3α/β, and total GSK3α/β in LNCaP and C4-2 cells at 24 h following exposure to control media or 25 μmol/L BZ36 inhibitor. E, the levels of PI(3,4,5)P3 produced were measured by ELISA on lipid extracts from LNCaP and C4-2 cells 24 h following treatment with BZ36 at 25 μmol/L or with control medium. Data are expressed in pmol. Columns, mean; bars, SD. F, rescue of BZ36-treated C4-2 cell proliferation by increasing PI(3,4,5)P3 amounts was measured by MTT assay. Forty-eight hours after treatment, the enzymatic reduction of MTT to formazan was quantified by absorbance reading at 540 nm. Columns, mean; bars, SD. G, rescue of BZ36-treated C4-2 cell signaling by increasing PI(3,4,5)P3 amounts was evaluated by immunoblot analysis of phospho-AKT, total AKT, phospho-GSK3α/β, and total GSK3α/β 24 h following exposure to 25 μmol/L BZ36 inhibitor. H, measurement of β-catenin luciferase reporter activity in LNCaP and C4-2 cells 24 h after exposure to control media or 25 μmol/L BZ36 inhibitor. Columns, mean; bars, SD. I, analysis of mRNA expression level variation of genes related to the Wnt/β-catenin signaling pathway in C4-2 cells 24 h following exposure to 25 μmol/L BZ36 inhibitor. Genes are grouped according to their belonging to cell surface receptors (members of the Frizzled-1 signaling pathway), glycosylated extracellular signaling molecules (members of the Frizzled-2 signaling pathway), Wnt binding antagonists and regulators of cell cycle, and proliferation and transcription relative to the Wnt signaling pathway. Genes that are upregulated are indicated in red and genes that are downregulated are indicated in blue. Data are representative of at least two independent experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 5.

    Inhibition of SCD1 activity decreases tumor growth of prostate cancer xenografts in vivo. Tumor volume progression of s.c. implanted LNCaP (A and B) or C4-2 (D and E) cells in nude athymic mice was measured weekly following daily i.p. injection with BZ36 at 80 mg/kg or with vehicle. A and D, points, mean tumor volume (mm3) from day 1 to day 21; bars, SE. B and E, values are expressed as the fold change to initial tumor volume (day 14/day 1). Quantification of PCNA immunostaining of proliferative LNCaP (C) and C4-2 (F) cells s.c. implanted 14 d following daily i.p. injection with BZ36 at 80 mg/kg or with vehicle. Six fields per section were analyzed for PCNA immunostaining indicative of cell proliferation. Sections of tumors of all mice were analyzed. At least 300 cells were counted per tumor. Data are representative of at least three independent experiments. G and H, the specific desaturation indexes 16:1n-7/16:0 and 18:1n-9/18:0 were analyzed in total lipids extracted from liver (G) and C4-2 tumor (H) tissues. Columns, mean; bars, SE. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 6.

    Inhibition of SCD1 activity restrains proliferation, increases apoptosis in Ras SV40–transformed MEFs in vitro, and decreases tumor growth of Ras SV40 MEF xenografts in vivo. A, proliferation of wild-type (WT), SV40-immortalized, or Ras SV40–transformed MEFs was measured with a hematocytometer at 24, 48, and 72 h following culture with control media or 25 μmol/L BZ36 inhibitor. B, SCD1 Δ9-desaturase activity was analyzed by measuring the conversion of exogenous 14C-saturated palmitic acid substrate into monounsaturated palmitoleic acid following exposure to control media or 25 μmol/L BZ36 inhibitor. C, proliferation of p53 knockout- or Ras-transformed p53 knockout MEFs was measured with a hematocytometer at 24, 48, and 72 h following culture with control media or 25 μmol/L BZ36 inhibitor. D, effect of the inhibition of SCD1 activity on apoptosis induction was analyzed by fluorescence-activated cell sorting by measuring the percentage of Annexin V–positive Ras SV40 MEFs at 24 h after exposure to control media or 25 μmol/L BZ36 inhibitor. E, tumor volume progression of s.c. implanted Ras SV40 MEFs in nude athymic mice was measured weekly following daily i.p. injection with BZ36 at 80 mg/kg or with vehicle. F, PCNA immunostaining of proliferative Ras SV40 MEFs s.c. implanted 14 d following daily i.p. injection with BZ36 at 80 mg/kg or with vehicle. Six fields per section were analyzed for PCNA immunostaining indicative of cell proliferation. Sections of tumors of all mice were analyzed. At least 300 cells were counted per tumor. G, the delay in tumor apparition following s.c. injection of 5 × 105 Ras SV40-tranformed MEFs was compared in mice that received daily injection of vehicle or BZ36 at 80 mg/kg during 1 wk before tumor cell injection. Columns, mean of at least two independent experiments done in triplicates; bars, SD. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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Molecular Cancer Therapeutics: 9 (6)
June 2010
Volume 9, Issue 6
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Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice
Vanessa Fritz, Zohra Benfodda, Geneviève Rodier, Corinne Henriquet, François Iborra, Christophe Avancès, Yves Allory, Alexandre de la Taille, Stéphane Culine, Hubert Blancou, Jean Paul Cristol, Françoise Michel, Claude Sardet and Lluis Fajas
Mol Cancer Ther June 1 2010 (9) (6) 1740-1754; DOI: 10.1158/1535-7163.MCT-09-1064

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Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice
Vanessa Fritz, Zohra Benfodda, Geneviève Rodier, Corinne Henriquet, François Iborra, Christophe Avancès, Yves Allory, Alexandre de la Taille, Stéphane Culine, Hubert Blancou, Jean Paul Cristol, Françoise Michel, Claude Sardet and Lluis Fajas
Mol Cancer Ther June 1 2010 (9) (6) 1740-1754; DOI: 10.1158/1535-7163.MCT-09-1064
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