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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

[18F]FDG uptake is enhanced in PC3-LUC orthotopic xenografts and TRAMP mouse models after systemic treatment with etomoxir. a) Coronal (left) and sagittal PET images of representative PC3-LUC orthotopic xenografts. Bioluminescence image on the right indicates where the tumor cells were growing; red and blue indicate high and low luciferase expression, respectively. In the left panels (coronal views), the arrows point to the primary tumor above the bladder (strong, circular white signal). In the right panels (sagittal views), arrows point to the ventral metastasis below the heart. This metastasis corresponds to upper-small signal in the adjacent bioluminescence image. b) Axial (left) and sagittal PET images of representative 24-week-old TRAMP mouse. Magnetic resonance images (sagittal and coronal) were used to anatomically visualize the increased prostate cancer growth, which extended into the seminal vesicles. White arrows point to tumor growth located posterior to the bladder. Bladder cannot be seen in the sagittal views, but it is visible (strong, circular white signal) in the axial views. MRI photographs: B (bladder), P (prostate), SV (seminal vesicles), T (testis).
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Fig5: [18F]FDG uptake is enhanced in PC3-LUC orthotopic xenografts and TRAMP mouse models after systemic treatment with etomoxir. a) Coronal (left) and sagittal PET images of representative PC3-LUC orthotopic xenografts. Bioluminescence image on the right indicates where the tumor cells were growing; red and blue indicate high and low luciferase expression, respectively. In the left panels (coronal views), the arrows point to the primary tumor above the bladder (strong, circular white signal). In the right panels (sagittal views), arrows point to the ventral metastasis below the heart. This metastasis corresponds to upper-small signal in the adjacent bioluminescence image. b) Axial (left) and sagittal PET images of representative 24-week-old TRAMP mouse. Magnetic resonance images (sagittal and coronal) were used to anatomically visualize the increased prostate cancer growth, which extended into the seminal vesicles. White arrows point to tumor growth located posterior to the bladder. Bladder cannot be seen in the sagittal views, but it is visible (strong, circular white signal) in the axial views. MRI photographs: B (bladder), P (prostate), SV (seminal vesicles), T (testis).

Mentions: Fig. 5a shows representative images of mice with orthotopic xenografts of PC3-luciferase cells. The PC3-LUC cells were surgically implanted in the right lobe of the mouse prostates. Mice in the images developed metastases in the abdomen that could be seen by bioluminescence. Only mice that showed luciferase expression were used for the PET scans. We observed a 2.7 ± 1.40-fold increase in NUV after etomoxir treatments for 24 h (P = 0.04). We also performed PET scans in TRAMP mice, which uniformly and spontaneously develop autochthonous (orthotopic) prostate tumors following the onset of puberty. Interestingly, like the human PCa tumors, the TRAMP tumors do not show increased expression of glucose transporters, which likely explains low [18F]FDG uptake [22]. Fig. 5b shows images of 24-week-old TRAMP mice, an interval at which growth of PCa is well documented [18]. The tumor behind the bladder (arrow) was significantly stronger after etomoxir treatment, and growth of prostate tissue into the seminal vesicles was observed in PET and MRI images. The increased NUV of TRAMP mice at 20 weeks was not remarkable (1.6-fold), but it was significant at 24 weeks when TRAMP tumor growth was larger (1.8 ± 0.2-fold, P = 0.004). Additional images of the orthotopic and TRAMP models are shown in ESM Fig. 2.Fig. 5


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)

[18F]FDG uptake is enhanced in PC3-LUC orthotopic xenografts and TRAMP mouse models after systemic treatment with etomoxir. a) Coronal (left) and sagittal PET images of representative PC3-LUC orthotopic xenografts. Bioluminescence image on the right indicates where the tumor cells were growing; red and blue indicate high and low luciferase expression, respectively. In the left panels (coronal views), the arrows point to the primary tumor above the bladder (strong, circular white signal). In the right panels (sagittal views), arrows point to the ventral metastasis below the heart. This metastasis corresponds to upper-small signal in the adjacent bioluminescence image. b) Axial (left) and sagittal PET images of representative 24-week-old TRAMP mouse. Magnetic resonance images (sagittal and coronal) were used to anatomically visualize the increased prostate cancer growth, which extended into the seminal vesicles. White arrows point to tumor growth located posterior to the bladder. Bladder cannot be seen in the sagittal views, but it is visible (strong, circular white signal) in the axial views. MRI photographs: B (bladder), P (prostate), SV (seminal vesicles), T (testis).
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Fig5: [18F]FDG uptake is enhanced in PC3-LUC orthotopic xenografts and TRAMP mouse models after systemic treatment with etomoxir. a) Coronal (left) and sagittal PET images of representative PC3-LUC orthotopic xenografts. Bioluminescence image on the right indicates where the tumor cells were growing; red and blue indicate high and low luciferase expression, respectively. In the left panels (coronal views), the arrows point to the primary tumor above the bladder (strong, circular white signal). In the right panels (sagittal views), arrows point to the ventral metastasis below the heart. This metastasis corresponds to upper-small signal in the adjacent bioluminescence image. b) Axial (left) and sagittal PET images of representative 24-week-old TRAMP mouse. Magnetic resonance images (sagittal and coronal) were used to anatomically visualize the increased prostate cancer growth, which extended into the seminal vesicles. White arrows point to tumor growth located posterior to the bladder. Bladder cannot be seen in the sagittal views, but it is visible (strong, circular white signal) in the axial views. MRI photographs: B (bladder), P (prostate), SV (seminal vesicles), T (testis).
Mentions: Fig. 5a shows representative images of mice with orthotopic xenografts of PC3-luciferase cells. The PC3-LUC cells were surgically implanted in the right lobe of the mouse prostates. Mice in the images developed metastases in the abdomen that could be seen by bioluminescence. Only mice that showed luciferase expression were used for the PET scans. We observed a 2.7 ± 1.40-fold increase in NUV after etomoxir treatments for 24 h (P = 0.04). We also performed PET scans in TRAMP mice, which uniformly and spontaneously develop autochthonous (orthotopic) prostate tumors following the onset of puberty. Interestingly, like the human PCa tumors, the TRAMP tumors do not show increased expression of glucose transporters, which likely explains low [18F]FDG uptake [22]. Fig. 5b shows images of 24-week-old TRAMP mice, an interval at which growth of PCa is well documented [18]. The tumor behind the bladder (arrow) was significantly stronger after etomoxir treatment, and growth of prostate tissue into the seminal vesicles was observed in PET and MRI images. The increased NUV of TRAMP mice at 20 weeks was not remarkable (1.6-fold), but it was significant at 24 weeks when TRAMP tumor growth was larger (1.8 ± 0.2-fold, P = 0.004). Additional images of the orthotopic and TRAMP models are shown in ESM Fig. 2.Fig. 5

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