CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer
Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compar...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/11/3431 |
| _version_ | 1797547516686761984 |
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| author | Molishree Joshi Jihye Kim Angelo D’Alessandro Emily Monk Kimberley Bruce Hanan Elajaili Eva Nozik-Grayck Andrew Goodspeed James C. Costello Isabel R. Schlaepfer |
| author_facet | Molishree Joshi Jihye Kim Angelo D’Alessandro Emily Monk Kimberley Bruce Hanan Elajaili Eva Nozik-Grayck Andrew Goodspeed James C. Costello Isabel R. Schlaepfer |
| author_sort | Molishree Joshi |
| collection | DOAJ |
| description | Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. Transcriptomic analysis identified ER stress, serine biosynthesis and lipid catabolism as significantly upregulated pathways in the OE versus KD cells. On the other hand, androgen response was significantly downregulated in OE cells. These changes associated with increased acyl-carnitines, serine synthesis and glutathione precursors in OE cells. Unexpectedly, OE cells showed increased mitochondrial ROS but when challenged with fatty acids and no androgens, the Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better antioxidant defenses with excess CPT1A expression. Public databases also showed decreased androgen response correlation with increased serine-related metabolism in advanced PCa. Lastly, worse progression free survival was observed with increased lipid catabolism and decreased androgen response. Excess CPT1A is associated with a ROS-mediated stress phenotype that can support PCa disease progression. This study provides a rationale for targeting lipid catabolic pathways for therapy in hormonal cancers. |
| first_indexed | 2024-03-10T14:45:10Z |
| format | Article |
| id | doaj.art-c94286ff1f624bd88db3eefd5faebf21 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:45:10Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c94286ff1f624bd88db3eefd5faebf212023-11-20T21:27:11ZengMDPI AGCancers2072-66942020-11-011211343110.3390/cancers12113431CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate CancerMolishree Joshi0Jihye Kim1Angelo D’Alessandro2Emily Monk3Kimberley Bruce4Hanan Elajaili5Eva Nozik-Grayck6Andrew Goodspeed7James C. Costello8Isabel R. Schlaepfer9Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADivision of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADivision of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADivision of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pediatrics Critical Care, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pediatrics Critical Care, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADivision of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USACancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. Transcriptomic analysis identified ER stress, serine biosynthesis and lipid catabolism as significantly upregulated pathways in the OE versus KD cells. On the other hand, androgen response was significantly downregulated in OE cells. These changes associated with increased acyl-carnitines, serine synthesis and glutathione precursors in OE cells. Unexpectedly, OE cells showed increased mitochondrial ROS but when challenged with fatty acids and no androgens, the Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better antioxidant defenses with excess CPT1A expression. Public databases also showed decreased androgen response correlation with increased serine-related metabolism in advanced PCa. Lastly, worse progression free survival was observed with increased lipid catabolism and decreased androgen response. Excess CPT1A is associated with a ROS-mediated stress phenotype that can support PCa disease progression. This study provides a rationale for targeting lipid catabolic pathways for therapy in hormonal cancers.https://www.mdpi.com/2072-6694/12/11/3431CPT1Aprostate cancerfatty acidsserineandrogen responseROS |
| spellingShingle | Molishree Joshi Jihye Kim Angelo D’Alessandro Emily Monk Kimberley Bruce Hanan Elajaili Eva Nozik-Grayck Andrew Goodspeed James C. Costello Isabel R. Schlaepfer CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer Cancers CPT1A prostate cancer fatty acids serine androgen response ROS |
| title | CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer |
| title_full | CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer |
| title_fullStr | CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer |
| title_full_unstemmed | CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer |
| title_short | CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer |
| title_sort | cpt1a over expression increases reactive oxygen species in the mitochondria and promotes antioxidant defenses in prostate cancer |
| topic | CPT1A prostate cancer fatty acids serine androgen response ROS |
| url | https://www.mdpi.com/2072-6694/12/11/3431 |
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