CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer.
Molishree JoshiJihye KimAngelo D'AlessandroEmily MonkKimberley BruceHanan ElajailiEva Nozik-GrayckAndrew GoodspeedJames C CostelloIsabel R SchlaepferPublished in: Cancers (2020)
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.
Keyphrases
- induced apoptosis
- reactive oxygen species
- prostate cancer
- cell cycle arrest
- oxidative stress
- poor prognosis
- fatty acid
- cell death
- healthcare
- dna damage
- cell proliferation
- clinical trial
- emergency department
- endoplasmic reticulum stress
- free survival
- metabolic syndrome
- signaling pathway
- adipose tissue
- binding protein
- cell therapy
- drug delivery
- risk assessment
- long non coding rna
- machine learning
- mental health
- cancer therapy
- mesenchymal stem cells
- stress induced
- bone marrow
- artificial intelligence
- skeletal muscle
- protein kinase