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Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

Schlaepfer IR, Glodé LM, Hitz CA, Pac CT, Boyle KE, Maroni P, Deep G, Agarwal R, Lucia SM, Cramer SD, Serkova NJ, Eckel RH - Mol Imaging Biol (2015)

Bottom Line: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines.Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro.PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, MS 8117 12801 E. 17th Ave, Room L18-8101D, Aurora, CO, 80045, USA, isabel.schlaepfer@ucdenver.edu.

ABSTRACT

Purpose: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose.

Procedures: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h.

Results: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

Conclusions: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

No MeSH data available.


Related in: MedlinePlus

Lipid oxidation is abundant in prostate cancer cells and interrupted by etomoxir. a) The effect of etomoxir (150 μM) on the [14C]oleic acid oxidation rate at the indicated times. Benign cells are BPH-1 and WPMY-1. a Benign (n = 6) vs. PCa (n = 9) without treatment, t test—P = 0.004. b Effect of 4 h treatment on oleate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P < 0.001), VCaP (P < 0.001), PC3 (P = 0.002). b) Effect of etomoxir on [14C]palmitate oxidation. c Benign (n = 6) vs. PCa (n = 9) with no treatment, t test—P = 0.006. d Effect of 4-h treatment on palmitate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P = 0.001), VCaP (P = 0.001), PC3 (P < 0.001). c) CPT1 isoform expression in PCa cells and BPH-1 benign line. Post hoc tests, *P ≤ 0.03 compared with BPH-1. #P ≤ 0.002 compared with BPH-1. d) CPT1A Western blot of cell lines examined. αTUB = tubulin loading control.
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Fig1: Lipid oxidation is abundant in prostate cancer cells and interrupted by etomoxir. a) The effect of etomoxir (150 μM) on the [14C]oleic acid oxidation rate at the indicated times. Benign cells are BPH-1 and WPMY-1. a Benign (n = 6) vs. PCa (n = 9) without treatment, t test—P = 0.004. b Effect of 4 h treatment on oleate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P < 0.001), VCaP (P < 0.001), PC3 (P = 0.002). b) Effect of etomoxir on [14C]palmitate oxidation. c Benign (n = 6) vs. PCa (n = 9) with no treatment, t test—P = 0.006. d Effect of 4-h treatment on palmitate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P = 0.001), VCaP (P = 0.001), PC3 (P < 0.001). c) CPT1 isoform expression in PCa cells and BPH-1 benign line. Post hoc tests, *P ≤ 0.03 compared with BPH-1. #P ≤ 0.002 compared with BPH-1. d) CPT1A Western blot of cell lines examined. αTUB = tubulin loading control.

Mentions: Fig. 1a shows the effect of etomoxir on the production of [14C]CO2 after incubation of the cells with [14C]oleate over 2 days. Note the increased oxidation rate in PCa cells (LNCaP, VCaP, and PC3) compared with the non-cancer controls (BPH-1 and WPMY-1 cells) at 0 h. VCaP cells oxidized the most oleic acid. Fig. 1b shows the effect of etomoxir on lipid oxidation rate with [14C]palmitate. In the absence of etomoxir treatment, LNCaP cells showed the highest rate of palmitic oxidation. Using RT-PCR, we observed that PCa cells have abundant expression of the CPT1A (liver) isoform, underscoring capacity of these PCa cells to oxidize fat; see Fig. 1c. VCaP cells showed the highest expression of CPT1A, which is parallel to the increased oleic acid oxidation capacity (Fig. 1a). Fig. 1d shows CPT1A protein expression of the cell lines examined.Fig. 1


Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

Schlaepfer IR, Glodé LM, Hitz CA, Pac CT, Boyle KE, Maroni P, Deep G, Agarwal R, Lucia SM, Cramer SD, Serkova NJ, Eckel RH - Mol Imaging Biol (2015)

Lipid oxidation is abundant in prostate cancer cells and interrupted by etomoxir. a) The effect of etomoxir (150 μM) on the [14C]oleic acid oxidation rate at the indicated times. Benign cells are BPH-1 and WPMY-1. a Benign (n = 6) vs. PCa (n = 9) without treatment, t test—P = 0.004. b Effect of 4 h treatment on oleate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P < 0.001), VCaP (P < 0.001), PC3 (P = 0.002). b) Effect of etomoxir on [14C]palmitate oxidation. c Benign (n = 6) vs. PCa (n = 9) with no treatment, t test—P = 0.006. d Effect of 4-h treatment on palmitate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P = 0.001), VCaP (P = 0.001), PC3 (P < 0.001). c) CPT1 isoform expression in PCa cells and BPH-1 benign line. Post hoc tests, *P ≤ 0.03 compared with BPH-1. #P ≤ 0.002 compared with BPH-1. d) CPT1A Western blot of cell lines examined. αTUB = tubulin loading control.
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Related In: Results  -  Collection

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Fig1: Lipid oxidation is abundant in prostate cancer cells and interrupted by etomoxir. a) The effect of etomoxir (150 μM) on the [14C]oleic acid oxidation rate at the indicated times. Benign cells are BPH-1 and WPMY-1. a Benign (n = 6) vs. PCa (n = 9) without treatment, t test—P = 0.004. b Effect of 4 h treatment on oleate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P < 0.001), VCaP (P < 0.001), PC3 (P = 0.002). b) Effect of etomoxir on [14C]palmitate oxidation. c Benign (n = 6) vs. PCa (n = 9) with no treatment, t test—P = 0.006. d Effect of 4-h treatment on palmitate oxidation in PCa cells. ANOVA P < 0.001, post hoc Tukey’s: LNCaP (P = 0.001), VCaP (P = 0.001), PC3 (P < 0.001). c) CPT1 isoform expression in PCa cells and BPH-1 benign line. Post hoc tests, *P ≤ 0.03 compared with BPH-1. #P ≤ 0.002 compared with BPH-1. d) CPT1A Western blot of cell lines examined. αTUB = tubulin loading control.
Mentions: Fig. 1a shows the effect of etomoxir on the production of [14C]CO2 after incubation of the cells with [14C]oleate over 2 days. Note the increased oxidation rate in PCa cells (LNCaP, VCaP, and PC3) compared with the non-cancer controls (BPH-1 and WPMY-1 cells) at 0 h. VCaP cells oxidized the most oleic acid. Fig. 1b shows the effect of etomoxir on lipid oxidation rate with [14C]palmitate. In the absence of etomoxir treatment, LNCaP cells showed the highest rate of palmitic oxidation. Using RT-PCR, we observed that PCa cells have abundant expression of the CPT1A (liver) isoform, underscoring capacity of these PCa cells to oxidize fat; see Fig. 1c. VCaP cells showed the highest expression of CPT1A, which is parallel to the increased oleic acid oxidation capacity (Fig. 1a). Fig. 1d shows CPT1A protein expression of the cell lines examined.Fig. 1

Bottom Line: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines.Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro.PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, MS 8117 12801 E. 17th Ave, Room L18-8101D, Aurora, CO, 80045, USA, isabel.schlaepfer@ucdenver.edu.

ABSTRACT

Purpose: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose.

Procedures: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h.

Results: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

Conclusions: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

No MeSH data available.


Related in: MedlinePlus