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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

Pharmacological block in fat oxidation results in glucose uptake in PCa cells. a) Normalized 2-[3H]DG uptake in patient-matched prostate-derived primary cells. Student’s t test: *vehicle-cancer compared with vehicle-benign P = 0.044. a P = 0.011 compared with benign-vehicle. #P = 0.009 compared with vehicle-cancer. b) Effect of 150 μM etomoxir on the 2-[3H]DG uptake of prostate-derived cell lines over 48 h. Bracket points to PCa cells. *Etomoxir effect at 24 h between cells lines, ANOVA P < 0.001. Post hoc tests: BPH-1 vs. LNCaP (P = 0.001), PC3 (P < 0.001), VCaP (P = 0.017), WPMY-1 (P = 0.03). Benign WPMY-1 vs. PC3 (P = 0.043). **Etomoxir effect at 48 h between cell lines, ANOVA P = 0.005. Post hoc tests: BPH-1 vs. LNCaP (P = 0.011), PC3 (P = 0.007).
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Fig3: Pharmacological block in fat oxidation results in glucose uptake in PCa cells. a) Normalized 2-[3H]DG uptake in patient-matched prostate-derived primary cells. Student’s t test: *vehicle-cancer compared with vehicle-benign P = 0.044. a P = 0.011 compared with benign-vehicle. #P = 0.009 compared with vehicle-cancer. b) Effect of 150 μM etomoxir on the 2-[3H]DG uptake of prostate-derived cell lines over 48 h. Bracket points to PCa cells. *Etomoxir effect at 24 h between cells lines, ANOVA P < 0.001. Post hoc tests: BPH-1 vs. LNCaP (P = 0.001), PC3 (P < 0.001), VCaP (P = 0.017), WPMY-1 (P = 0.03). Benign WPMY-1 vs. PC3 (P = 0.043). **Etomoxir effect at 48 h between cell lines, ANOVA P = 0.005. Post hoc tests: BPH-1 vs. LNCaP (P = 0.011), PC3 (P = 0.007).

Mentions: We next examined prostate biopsy-derived primary cells. Etomoxir treatment (6 h) resulted in significant increase in glucose uptake (1.76-fold, P < 0.05) in patient-derived benign prostate cells, but the effect was stronger in the adjacent tumor-derived cells (2.7-fold, P < 0.01); see Fig. 3a. We then extended these studies to PCa (LNCaP, VCaP, PC3) and benign (BPH-1, WPMY-1) cell lines. Overall, PCa cell lines showed progressive increase in glucose uptake compared with no treatment (0 h), ANOVA, P < 0.01; see Fig. 3b. Interestingly, benign BPH-1 and WPMY-1 did not show a significant increase in 2DG uptake with etomoxir; in fact, BPH-1 cells showed a slight decrease by 24 h.Fig. 3


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)

Pharmacological block in fat oxidation results in glucose uptake in PCa cells. a) Normalized 2-[3H]DG uptake in patient-matched prostate-derived primary cells. Student’s t test: *vehicle-cancer compared with vehicle-benign P = 0.044. a P = 0.011 compared with benign-vehicle. #P = 0.009 compared with vehicle-cancer. b) Effect of 150 μM etomoxir on the 2-[3H]DG uptake of prostate-derived cell lines over 48 h. Bracket points to PCa cells. *Etomoxir effect at 24 h between cells lines, ANOVA P < 0.001. Post hoc tests: BPH-1 vs. LNCaP (P = 0.001), PC3 (P < 0.001), VCaP (P = 0.017), WPMY-1 (P = 0.03). Benign WPMY-1 vs. PC3 (P = 0.043). **Etomoxir effect at 48 h between cell lines, ANOVA P = 0.005. Post hoc tests: BPH-1 vs. LNCaP (P = 0.011), PC3 (P = 0.007).
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Fig3: Pharmacological block in fat oxidation results in glucose uptake in PCa cells. a) Normalized 2-[3H]DG uptake in patient-matched prostate-derived primary cells. Student’s t test: *vehicle-cancer compared with vehicle-benign P = 0.044. a P = 0.011 compared with benign-vehicle. #P = 0.009 compared with vehicle-cancer. b) Effect of 150 μM etomoxir on the 2-[3H]DG uptake of prostate-derived cell lines over 48 h. Bracket points to PCa cells. *Etomoxir effect at 24 h between cells lines, ANOVA P < 0.001. Post hoc tests: BPH-1 vs. LNCaP (P = 0.001), PC3 (P < 0.001), VCaP (P = 0.017), WPMY-1 (P = 0.03). Benign WPMY-1 vs. PC3 (P = 0.043). **Etomoxir effect at 48 h between cell lines, ANOVA P = 0.005. Post hoc tests: BPH-1 vs. LNCaP (P = 0.011), PC3 (P = 0.007).
Mentions: We next examined prostate biopsy-derived primary cells. Etomoxir treatment (6 h) resulted in significant increase in glucose uptake (1.76-fold, P < 0.05) in patient-derived benign prostate cells, but the effect was stronger in the adjacent tumor-derived cells (2.7-fold, P < 0.01); see Fig. 3a. We then extended these studies to PCa (LNCaP, VCaP, PC3) and benign (BPH-1, WPMY-1) cell lines. Overall, PCa cell lines showed progressive increase in glucose uptake compared with no treatment (0 h), ANOVA, P < 0.01; see Fig. 3b. Interestingly, benign BPH-1 and WPMY-1 did not show a significant increase in 2DG uptake with etomoxir; in fact, BPH-1 cells showed a slight decrease by 24 h.Fig. 3

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