CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer

Cancers - Tập 12 Số 11 - Trang 3431
Molishree Joshi1, Jihye Kim2, Angelo D’Alessandro3,4, Emily Monk2, Kimberley D. Bruce5, Hanan Elajaili6, Eva Nozik‐Grayck6, Andrew Goodspeed1,4, James C. Costello1,4, Isabel R. Schlaepfer2
1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
2Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
3Department of Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
4University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
5Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
6Department of Pediatrics Critical Care, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Tóm tắt

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.

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Cancers

Tập 12 Số 11

3431

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