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1.
bioRxiv ; 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38903086

ABSTRACT

Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 mut /IDH2 mut ) and 1p/19q co-deletions. Previously, we reported that in IDH1 mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDH mut -specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1 mut oligodendroglioma. We demonstrated an IDH1 mut -specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1 mut and should be considered in the future.

2.
Cell Death Dis ; 14(1): 57, 2023 01 24.
Article in English | MEDLINE | ID: mdl-36693836

ABSTRACT

There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies.


Subject(s)
Carnitine O-Palmitoyltransferase , Neoplasms , Humans , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Hypoxia/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/physiopathology , Neurons/metabolism , Oxidation-Reduction
3.
Int J Mol Sci ; 24(2)2023 Jan 04.
Article in English | MEDLINE | ID: mdl-36674468

ABSTRACT

Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy.


Subject(s)
Breast Neoplasms , Carnitine O-Palmitoyltransferase , Drug Resistance, Neoplasm , Female , Humans , Anthracyclines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Cell Membrane/metabolism , Down-Regulation
4.
Biochem Pharmacol ; 177: 113959, 2020 07.
Article in English | MEDLINE | ID: mdl-32272110

ABSTRACT

Breast cancer is the most prevalent type of tumor and the second leading cause of death due to cancer among women. Although screening methods, diagnosis and therapeutic options have improved in the last decade, chemoresistance remains an important challenge. There is evidence relating breast cancer resistance with signaling pathways involving hormone and growth receptors, survival, apoptosis and the activation of efflux pumps. However, the resistance mechanisms linked to drug uptake are poorly understood, despite it often being observed that the drug content is lower in resistant cancer cells and that the entry of the drug into these cells is a limiting process for the subsequent therapeutic effect.In this review, we provide an overview of drug uptake-based resistance mechanisms developed by cancer cells in the four main types of chemotherapy used in breast cancer: anthracyclines, taxanes, oxazaphosphorines and platinum-based drugs. The contribution of tumor microenvironment to reduced drug-uptake and multidrug resistance is also analyzed. As a developing field, nanomedicine-based approaches provide promising opportunities to improve drug specific targeting, cell interaction and uptake into cancer cells. The endocytic-mediated pathways attributed to the different types of nanoformulations as well as the contribution of nanotherapeutics to overcoming chemoresistance affecting drug uptake in breast cancer will be described. New approaches focusing on drug uptake mechanisms could improve breast cancer chemotherapy, obtaining better dose-response outcomes and reducing toxic side effects.


Subject(s)
Anthracyclines/therapeutic use , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Oxazines/therapeutic use , Platinum Compounds/therapeutic use , Taxoids/therapeutic use , Anthracyclines/pharmacokinetics , Breast Neoplasms/metabolism , Female , Humans , Nanomedicine/methods , Nanomedicine/trends , Oxazines/pharmacokinetics , Platinum Compounds/pharmacokinetics , Taxoids/pharmacokinetics , Tumor Microenvironment/drug effects
5.
Sci Rep ; 8(1): 6997, 2018 05 03.
Article in English | MEDLINE | ID: mdl-29725060

ABSTRACT

Human mesenchymal stem cells (hMSCs) are widely used in regenerative medicine. In some applications, they must survive under low nutrient conditions engendered by avascularity. Strategies to improve hMSCs survival may be of high relevance in tissue engineering. Carnitine palmitoyltransferase 1 C (CPT1C) is a pseudoenzyme exclusively expressed in neurons and cancer cells. In the present study, we show that CPT1C is also expressed in hMSCs and protects them against glucose starvation, glycolysis inhibition, and oxygen/glucose deprivation. CPT1C overexpression in hMSCs did not increase fatty acid oxidation capacity, indicating that the role of CPT1C in these cells is different from that described in tumor cells. The increased survival of CPT1C-overexpressing hMSCs observed during glucose deficiency was found to be the result of autophagy enhancement, leading to a greater number of lipid droplets and increased intracellular ATP levels. In fact, inhibition of autophagy or lipolysis was observed to completely block the protective effects of CPT1C. Our results indicate that CPT1C-mediated autophagy enhancement in glucose deprivation conditions allows a greater availability of lipids to be used as fuel substrate for ATP generation, revealing a new role of CPT1C in stem cell adaptation to low nutrient environments.


Subject(s)
Autophagy , Carnitine O-Palmitoyltransferase/metabolism , Glucose/metabolism , Mesenchymal Stem Cells/physiology , Adenosine Triphosphate/metabolism , Cell Survival , Cells, Cultured , Energy Metabolism , Fatty Acids/metabolism , Humans , Lipolysis , Oxidation-Reduction
6.
Behav Brain Res ; 256: 291-7, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-23973755

ABSTRACT

Carnitine palmitoyltransferase 1c (CPT1C), a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions, but its only known functions to date are involved in the hypothalamic control of energy homeostasis and in hippocampus-dependent spatial learning. To identify other physiological and behavioral functions of this protein, we performed a battery of neurological tests on Cpt1c-deficient mice. The animals showed intact autonomic and sensory systems, but some motor disturbances were observed. A more detailed study of motor function revealed impaired coordination and gait, severe muscle weakness, and reduced daily locomotor activity. Analysis of motor function in these mice at ages of 6-24 weeks showed that motor disorders were already present in young animals and that impairment increased progressively with age. Analysis of CPT1C expression in different motor brain areas during development revealed that CPT1C levels were low from birth to postnatal day 10 and then rapidly increased peaking at postnatal day 21, which suggests that CPT1C plays a relevant role in motor function during and after weaning. As CPT1C is known to regulate ceramide levels, we measured these biolipids in different motor areas in adult mice. Cerebellar, striatum, and motor cortex extracts from Cpt1c knockout mice showed reduced levels of ceramide and its derivative sphingosine when compared to wild-type animals. Our results indicate that altered ceramide metabolism in motor brain areas induced by Cpt1c deficiency causes progressive motor dysfunction from a young age.


Subject(s)
Brain/growth & development , Brain/physiopathology , Carnitine O-Palmitoyltransferase/deficiency , Movement Disorders/physiopathology , Animals , Animals, Newborn , Blotting, Western , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Ceramides/metabolism , Disease Progression , Gait/physiology , Male , Mice, Knockout , Motor Activity/physiology , Muscle Weakness/physiopathology , Neurologic Examination , Reflex/physiology , Rotarod Performance Test , Sphingosine/metabolism
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