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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

Knockdown of CPT1A results in decreased lipid oxidation and increased glucose uptake. a) Western blot of lysates of LNCaP CPT1A KD clones (#36279 and 36281) exposed to etomoxir for 24 h. C = control clone, V = vehicle-treated, E = etomoxir-treated. b) [14C]Palmitic acid oxidation rate of the control and CPT1A-KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.01 compared with control clone, ^P ≤ 0.004 compared with vehicle treatment. c) Normalized 2-[3H] DG uptake in the LNCaP CPT1A KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.001, compared with vehicle treatment, ^P ≤ 0.001 compared with control clone.
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Fig2: Knockdown of CPT1A results in decreased lipid oxidation and increased glucose uptake. a) Western blot of lysates of LNCaP CPT1A KD clones (#36279 and 36281) exposed to etomoxir for 24 h. C = control clone, V = vehicle-treated, E = etomoxir-treated. b) [14C]Palmitic acid oxidation rate of the control and CPT1A-KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.01 compared with control clone, ^P ≤ 0.004 compared with vehicle treatment. c) Normalized 2-[3H] DG uptake in the LNCaP CPT1A KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.001, compared with vehicle treatment, ^P ≤ 0.001 compared with control clone.

Mentions: Since etomoxir targets the CPT-1 enzyme [19, 20], we used shRNAs to decrease CPT1A expression in LNCaP cells and mimic the pharmacological effects of etomoxir. We obtained two clones with specific knockdown (KD) of CPT1A, as shown in Fig. 2a, which surprisingly responded to 24 h etomoxir treatment by increasing CPT1A protein expression, likely reflecting a compensatory response. The 36279 and 36281 CPT1A KD clones decreased palmitate oxidation by 60 % and 25 %, respectively, when compared with control-transfected cells; see Fig. 2b. These effects were further decreased by addition of etomoxir in clone 36281 but not in 39279, suggesting maximal inhibition of beta-oxidation in the 36279 clone, which had the lowest CPT1A expression.Fig. 2


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)

Knockdown of CPT1A results in decreased lipid oxidation and increased glucose uptake. a) Western blot of lysates of LNCaP CPT1A KD clones (#36279 and 36281) exposed to etomoxir for 24 h. C = control clone, V = vehicle-treated, E = etomoxir-treated. b) [14C]Palmitic acid oxidation rate of the control and CPT1A-KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.01 compared with control clone, ^P ≤ 0.004 compared with vehicle treatment. c) Normalized 2-[3H] DG uptake in the LNCaP CPT1A KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.001, compared with vehicle treatment, ^P ≤ 0.001 compared with control clone.
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Related In: Results  -  Collection

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Fig2: Knockdown of CPT1A results in decreased lipid oxidation and increased glucose uptake. a) Western blot of lysates of LNCaP CPT1A KD clones (#36279 and 36281) exposed to etomoxir for 24 h. C = control clone, V = vehicle-treated, E = etomoxir-treated. b) [14C]Palmitic acid oxidation rate of the control and CPT1A-KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.01 compared with control clone, ^P ≤ 0.004 compared with vehicle treatment. c) Normalized 2-[3H] DG uptake in the LNCaP CPT1A KD clones, ANOVA P < 0.001. Post hoc tests, *P ≤ 0.001, compared with vehicle treatment, ^P ≤ 0.001 compared with control clone.
Mentions: Since etomoxir targets the CPT-1 enzyme [19, 20], we used shRNAs to decrease CPT1A expression in LNCaP cells and mimic the pharmacological effects of etomoxir. We obtained two clones with specific knockdown (KD) of CPT1A, as shown in Fig. 2a, which surprisingly responded to 24 h etomoxir treatment by increasing CPT1A protein expression, likely reflecting a compensatory response. The 36279 and 36281 CPT1A KD clones decreased palmitate oxidation by 60 % and 25 %, respectively, when compared with control-transfected cells; see Fig. 2b. These effects were further decreased by addition of etomoxir in clone 36281 but not in 39279, suggesting maximal inhibition of beta-oxidation in the 36279 clone, which had the lowest CPT1A expression.Fig. 2

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