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

Joshi, Molishree; Kim, Jihye; D’Alessandro, Angelo; Monk, Emily; Bruce, Kimberley D.; Elajaili, Hanan; Nozik‐Grayck, Eva; Goodspeed, Andrew; Costello, James C.; Schlaepfer, Isabel R.

doi:10.3390/cancers12113431

Cited by 33 publications

(27 citation statements)

References 63 publications

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“…Cpt1a fuels lipid β-oxidation by producing acyl-carnitines in the mitochondria ( 39 ). It was recently demonstrated that in prostate cancer cell models, overexpression of Cpt1a is associated with a significant increase in intracellular lipase activity ( 40 ), a step that liberates fatty acids from triglyceride stores, which can then be used for β-oxidation ( 41 ). Consequently, overexpression of Cpt1a increases free fatty acid (FFA) content in these cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity

Sáez-Orellana¹,

Leroy²,

Ribeiro³

et al. 2021

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Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in AD physiopathology impairs lipid synthesis needed for cortical networks activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation are inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains.Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by PPARα specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.

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Section: Resultsmentioning

confidence: 99%

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity

Sáez-Orellana¹,

Leroy²,

Ribeiro³

et al. 2021

JCI Insight

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“…The authors demonstrated that androgen withdrawal (which mimics the standard of care therapy for metastatic PCa) increases CPT-1A expression and FAO activity, which supports CRPC growth and antiandrogen resistance by supplying acetyl groups for histone acetylation ( 117 ). In a follow-up study, the authors showed that CPT-1A overexpression promotes antioxidant defenses, which foster PCa progression ( 118 ). Finally, last year, the group put forward the involvement of FAO in immunomodulation.…”

Section: Lipid Metabolism Rewiring In Pca Development and Progressionmentioning

confidence: 99%

“…Finally, last year, the group put forward the involvement of FAO in immunomodulation. Using the TRAMPC1 PCa model, the authors demonstrated that FAO inhibition with ranolazine decreases Tim3 content in CD8+ tumor-infiltrating T cells, increases macrophages, and decreases blood myeloid immunosuppressive monocytes, suggesting that targeting FAO stimulates anti-cancer immunity ( 118 ).…”

Section: Lipid Metabolism Rewiring In Pca Development and Progressionmentioning

confidence: 99%

Prostate Cancer Progression: as a Matter of Fats

2021

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Advanced prostate cancer (PCa) represents the fifth cause of cancer death worldwide. Although survival has improved with second-generation androgen signaling and Parp inhibitors, the benefits are not long-lasting, and new therapeutic approaches are sorely needed. Lipids and their metabolism have recently reached the spotlight with accumulating evidence for their role as promoters of PCa development, progression, and metastasis. As a result, interest in targeting enzymes/transporters involved in lipid metabolism is rapidly growing. Moreover, the use of lipogenic signatures to predict prognosis and resistance to therapy has been recently explored with promising results. Despite the well-known association between obesity with PCa lethality, the underlying mechanistic role of diet/obesity-derived metabolites has only lately been unveiled. Furthermore, the role of lipids as energy source, building blocks, and signaling molecules in cancer cells has now been revisited and expanded in the context of the tumor microenvironment (TME), which is heavily influenced by the external environment and nutrient availability. Here, we describe how lipids, their enzymes, transporters, and modulators can promote PCa development and progression, and we emphasize the role of lipids in shaping TME. In a therapeutic perspective, we describe the ongoing efforts in targeting lipogenic hubs. Finally, we highlight studies supporting dietary modulation in the adjuvant setting with the purpose of achieving greater efficacy of the standard of care and of synthetic lethality. PCa progression is “a matter of fats”, and the more we understand about the role of lipids as key players in this process, the better we can develop approaches to counteract their tumor promoter activity while preserving their beneficial properties.

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“…Urological Cancer 2020 contains three reviews [ 31 , 32 , 33 ] and seven articles [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ] about prostate cancer. Sarkar et al [ 31 ] reviewed the intimate mechanisms of angiogenesis in prostate cancer and their possible blockade to maximize benefits minimizing toxicity.…”

mentioning

confidence: 99%

“…The authors considered this effect as a potential target to develop new therapeutic strategies in castration-resistant prostate cancers. Transcriptomic and metabolomic analyses of LNCaP-C4-2 cell lines with depleted and increased CPT1A (carnitine palmitoyl transferase 1) expression, respectively, were investigated [ 40 ]. CPT1A plays an important role in the adaptation to stress and antioxidant production and is an enzyme involved in lipid catabolism and may be critically involved in promoting neuroendocrine differentiation in prostate cancer cells.…”

mentioning

confidence: 99%