Accumulation of Palmitoylcarnitine and Its Effect on Pro‐Inflammatory Pathways and Calcium Influx in Prostate Cancer

Al-Bakheit, Ala’a; Τράκα, Μαρία; Saha, Shikha; Mithen, Richard; Melchini, Antonietta

doi:10.1002/pros.23222

Cited by 26 publications

(22 citation statements)

References 47 publications

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“…These changes include an upregulation metabolites involved in de novo lipid biosynthesis [48] and fatty acid β-oxidation [49]. As consequence, it has been shown the accumulation in the prostatic tissue of acyl carnitines, which are intermediates of fatty acid oxidation [50]. In agreement with this alteration, we found increased levels of acyl carnitines in the urinary EVs from PCa patients.…”

Section: Discussionsupporting

confidence: 79%

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Clos-García

Loizaga-Iriarte

Zúñiga-García

et al. 2018

J of Extracellular Vesicle

117

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Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultra-high-performance liquid chromatography–mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.

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Section: Discussionsupporting

confidence: 79%

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Clos-García

Loizaga-Iriarte

Zúñiga-García

et al. 2018

J of Extracellular Vesicle

117

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“…Similar effects on IL‐6 secretion and cell stress were observed when PC3 prostate cancer cells were treated with 50 μ mol/L palmitoylcarnitine; intracellular calcium was increased in those cells at ≥5 μ mol/L (Al‐Bakheit et al. ).…”

Section: Introductionmentioning

confidence: 59%

“…; Al‐Bakheit et al. ). Diminution of LCAC production in myocytes, heart or muscle tissue, through treatment with 2‐tetradecylglycidic acid (TDGA) CPT1 inhibitor (Vogel‐van et al.…”

Section: Discussionmentioning

confidence: 99%

Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long‐chain fatty acid oxidation disorders

et al. 2019

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Excessive cellular accumulation or exposure to lipids such as long‐chain acylcarnitines ( LCAC s), ceramides, and others is implicated in cell stress and inflammation. Such a situation might manifest when there is a significant mismatch between long‐chain fatty acid ( LCFA ) availability versus storage and oxidative utilization; for example, in cardiac ischemia, increased LCAC s may contribute to tissue cell stress and infarct damage. Perturbed LCFA β ‐oxidation is also seen in fatty acid oxidation disorders ( FAOD s). FAOD s typically manifest with fasting‐ or stress‐induced symptoms, and patients can manage many symptoms through control of diet and physical activity. However, episodic clinical events involving cardiac and skeletal muscle myopathies are common and can present without an obvious molecular trigger. We have speculated that systemic or tissue‐specific lipotoxicity and activation of inflammation pathways contribute to long‐chain FAOD pathophysiology. With this in mind, we characterized inflammatory phenotype (14 blood plasma cytokines) in resting, overnight‐fasted (~10 h), or exercise‐challenged subjects with clinically well‐controlled long‐chain FAOD s ( n = 12; 10 long‐chain 3‐hydroxyacyl‐CoA dehydrogenase [ LCHAD ]; 2 carnitine palmitoyltransferase 2 [ CPT 2]) compared to healthy controls ( n = 12). Across experimental conditions, concentrations of three cytokines were modestly but significantly increased in FAOD ( IFN γ , IL ‐8, and MDC ), and plasma levels of IL ‐10 (considered an inflammation‐dampening cytokine) were significantly decreased. These novel results indicate that while asymptomatic FAOD patients do not display gross body‐wide inflammation even after moderate exercise, β ‐oxidation deficiencies might be associated with chronic and subtle activation of “sterile inflammation.” Further studies are warranted to determine if inflammation is more apparent in poorly controlled long‐chain FAOD or when long‐chain FAOD ‐associated symptoms are present.

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“…Meanwhile, the increased proliferation induced by LPCAT1 could be reversed by androgen depletion in vivo and in vitro, suggesting that the increased proliferation induced by LPCAT1 was through shifting into nucleus in an androgen-dependent manner. It is possible that the increase in Ca 2+ influx promoted by DHT [22] is a factor for LPCAT1 re-translocation for the activation of RNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: LPCAT1 promotes castration resistant prostate cancer progression by increasing PAF release and mRNA synthesis

Xu¹,

Cheng²,

Yu³

et al. 2018

Oncotarget

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Our previous study demonstrated that compared with primary prostate cancer (PCa), Lysophosphatidylcholine Acyltransferase1 (LPCAT1) was overexpressed in castration resistant prostate cancer (CRPC) and regulated by androgen through the Wnt-dependent signaling pathway. However, its role in the progression of CRPC remains unclear. The aim of the present study was to explore the roles of LPCAT1 on CRPC progression and the underlying molecular mechanism. It was found that LPCAT1 promoted to the progression of CRPC in terms of proliferation, invasion and migration in vitro and in vivo. The decreased invasion and migration of CRPC cells induced by LPCAT1 silencing could be reversed by platelet activating factor acetylhydrolase (PAF-AH) and PAFR antagonist ABT-491, while the increased invasion and migration of CRPC cells induced by LPCAT1 overexpression can be reversed by exogenous PAF. However, the fluctuated ability of cell proliferation induced by LPCAT1 can't be influenced by PAF-AH or exogenous PAF. Effect of LPCAT1 on increasing growth of CRPC cells by shifting into nucleus to palmitorylate Histone H4 in an androgen dependent-manner, thus enhancing mRNA synthesis. In addition, the increased expression of LPCAT1 in CRPC cells impaired sensitivity of cancer cells to paclitaxel (PTX) treatment. These results suggest that LPCAT1 may be an effective therapeutic target for CRPC therapy, though more studies are required to deeply elucidate the mechanism underlying role of LPCAT1 in promoting the progression of CRPC.

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Accumulation of Palmitoylcarnitine and Its Effect on Pro‐Inflammatory Pathways and Calcium Influx in Prostate Cancer

Cited by 26 publications

References 47 publications

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long‐chain fatty acid oxidation disorders

WITHDRAWN: LPCAT1 promotes castration resistant prostate cancer progression by increasing PAF release and mRNA synthesis

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