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

Simple Summary: Prostate cancer (PCa) is the most common cancer in men and the second highest contributor to cancer deaths. Targeting lipid catabolism enzymes in PCa may offer new avenues for therapeutic approaches. During the last decade, carnitine palmitoyl transferase I (CPT1A) has been identified as a potential therapeutic target for a growing list of cancers. In this study, we have tested the hypothesis that excess CPT1A plays a key role in supporting adaptation to stress and antioxidant defense production in PCa cells. Specifically, we have studied molecular differences between CPT1A gain and loss of function models, revealing genetic and metabolic vulnerabilities that could be targeted to avoid progression to neuroendocrine differentiation, a lethal form of the disease. Examining public datasets, we have also found that excess CPT1A expression leads to worse progression-free survival in PCa patients. 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. [ABSTRACT FROM AUTHOR]