Implication of Ceramide Kinase/C1P in Cancer Development and Progression

Camacho, Laura; Ouro, Alberto; Gómez-Larrauri, Ana; Carracedo, Arkaitz; Gómez-Muñoz, Antonio

doi:10.3390/cancers14010227

Cited by 17 publications

(13 citation statements)

References 108 publications

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“…Sphingomyelin is produced by ceramide and phosphatidylcholine, and the reaction is catalyzed by sphingomyelin synthase ( Morigny et al, 2020 ). Stress response, differentiation, proliferation, apoptosis and migration of tumor cells are all regulated by sphingolipids receptor, especially Cer, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) ( Pchejetski et al, 2008 ; Guillermet-Guibert et al, 2009 ; Huang et al, 2013 ; Gomez-Larrauri et al, 2020 ; Presa et al, 2020 ; Camacho et al, 2022 ). What’s more, sphingolipids are the most important elements of the lipid raft.…”

Section: Discussionmentioning

confidence: 99%

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

Zhou

Zheng

et al. 2022

Front. Pharmacol.

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Background: Psychologic depression is a pivotal pathological characteristic and has been shown to promote prostate cancer (PCa) progression. Chaihu-Shugan-San (CSS), a well-known Chinese herbal decoction, exhibits efficacy in the treatment of stress-accelerated PCa. However, the underlying mechanism of CSS in resisting PCa growth is still unknown, and further study is needed.Objective: To evaluate the effects of CSS on stress-accelerated PCa in a BALB/C nude mice model and to investigate the underlying mechanisms.Methods: PC-3 cells were implanted into BALB/C nude mice, and the stressed mice were exposed to chronic unpredictable mild stress (CUMS) to study the effects of CSS. The PCa growth were evaluated by tumor volume and tumor weight. Analyses of depression-like behaviors were evaluated by sucrose consumption test, tail suspension test and open field test. Network pharmacology was used to analyze the potential targets and signaling pathways of CSS against PCa. Untargeted lipidomics were used to analyze the serum lipid profiles and further elucidate the possible mechanism.Results: In the CUMS stressed PCa mice, CSS can restrain tumor growth with reduced tumor volume and tumor weight, and depression-like behaviors with increased sucrose consumption, reduced immobility duration, and increased total distance and center distance. Network pharmacology suggested that the lipid metabolism-related pathways are the most likely potential targets of CSS against PCa. Using untargeted lipidomics analysis, 62 lipids were found to have significant changes in PCa mice under CUMS treatment. The levels of glycerophospholipids containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylglycerol (PG), except PC (18:0_22:6) and PC (18:0_20:4), were significantly increased. Likewise, the levels of all sphingolipids (including sphingomyelin (SM), ceramides (Cer) and hexosyl-1-ceramide (Hex1Cer)) and diglyceride (DG) (32:1e) were significantly increased. CSS water extract was found to contribute to restore 32 lipids including 6 sphingolipids, 25 glycerophospholipids and 1 glyceride.Conclusion: This study is the first to delineate the lipid profile of stressed PCa BALB/C nude mice using untargeted lipidomics analysis. CSS restrained tumor growth and ameliorated depression-like behaviors by reprogramming lipid metabolism. Intervention of lipid metabolism could be a preventive and therapeutic approach for PCa patients with depression.

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Section: Discussionmentioning

confidence: 99%

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

Zhou

Zheng

et al. 2022

Front. Pharmacol.

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“…1b). As CerK level is closely associated with ceramide and C1P [9], we assessed ceramide level using LC-MS and C1P level using ELISA approaches in both tissue types. Compared to normal ovarian cells, we found that ceramide and C1P levels were decreased by ∼30% and ∼60% in ovarian cancer, respectively (Fig.…”

Section: Expression Analysis Of Cerk Ceramide and C1p In Ovarian Cancermentioning

confidence: 99%

“…Ceramides are the hub of sphingolipid metabolism, are key lipids in energetic-metabolic pathways and signaling cascades, and have been linked to promotion of apoptosis and drug sensitivity [7,8]. In contrast, ceramide 1-phosphate (C1P) is a pleiotropic bioactive sphingolipid that facilitates growth, survival, senescence, and metastasis in cancer progression [9,10]. Ceramide kinase (CerK) is an enzyme that is responsible for C1P biosynthesis through phosphorylating ceramide [11].…”

Section: Introductionmentioning

confidence: 99%

“…Ceramide kinase (CerK) is an enzyme that is responsible for C1P biosynthesis through phosphorylating ceramide [11]. As a regulator of both ceramide and C1P, CerK has been well recognized in promoting cancer cell growth, survival, recurrence, and dissemination [9,12,13]. NVP-231, a specific and potent inhibitor of CerK, inhibits lung and breast cancer cell proliferation [14].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Ceramide Kinase Is Effective against Cisplatin-Resistant Ovarian Cancer Cells by Regulating Ceramide and C1P Levels

Zou¹,

Jiang²

2023

Gynecol Obstet Invest

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Objective: Chemoresistance in ovarian cancer results in treatment failure, yet underlying mechanisms that regulate chemoresistance remain largely unclear. There is emerging evidence relating ovarian cancer drug resistance with bioactive sphingolipids and regulation of sphingolipid metabolism. This work investigated the expression and function of ceramide kinase (CerK), a lipid kinase that regulate central bioactive sphingolipids, in ovarian cancer, as well as the therapeutic potential of targeting CERK. Design: The level of ceramide, C1P and Cerk in ovarian cancer and normal counterpart were measured. Functions of Cerk in ovarian cancer was examined. Materials, Setting, Methods: Immunohistochemistry, ELISA and mass spectrometry methods were used to measure the level of ceramids, C1P and CerK in primary tissues. Proliferation and apoptosis assays were performed in ovarian cancer cells after CERK depletion, CERK overexpression and NVP-231 treatment in the absence or presence of cisplatin. Results: Compared to normal ovarian cells, CerK and its-mediated bioactive sphingolipids ceramide and ceramide 1-phosphate (C1P) were decreased in ovarian cancer tissues. Interestingly, cisplatin-resistant ovarian cancer cells displayed increased CerK, decreased ceramide and increased C1P, and furthermore that CerK level was closely associated with ceramide and C1P levels in ovarian cancer cells. Functional analysis demonstrated that CerK overexpression was sufficient to promote growth and confer chemo-resistance in ovarian cancer cells. CerK inhibition via both genetic and pharmacological approaches suppressed growth and induced apoptosis in cisplatin-resistant cells, and furthermore that significantly augmented cisplatin’s efficacy. Limitations: The functional analysis of C1P was performed in in vitro ovarian cancer cells. In vivo studies were needed to further confirm the effects of CERK inhibition. Conclusions: Our work is the first to show the critical role of CerK as the underlying mechanism of ovarian cancer chemoresistance, through regulating ceramide and C1P.

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“…CerK is a calcium ion-dependent enzyme that catalyzes the production of C1P in cells. Intracellular C1P can perform a variety of biological functions, including the stimulation of tumor cell growth, the stimulation of VEGF release, the inhibition of tumor cell apoptosis, the promotion of tumor inflammation, the regulation of angiogenesis, and the stimulation of tumor cell migration ( 83 – 85 ). C1P regulates the invasion and migration of different types of cancer cells, including breast, lung, prostate, pancreas or leukemia cells ( 83 ).…”

Section: The Value Of Sphingolipid Metabolism In Cancermentioning

confidence: 99%

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

Wang

et al. 2022

Front. Oncol.

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Biologically active sphingolipids are closely related to the growth, differentiation, aging, and apoptosis of cancer cells. Some sphingolipids, such as ceramides, are favorable metabolites in the sphingolipid metabolic pathway, usually mediating antiproliferative responses, through inhibiting cancer cell growth and migration, as well as inducing autophagy and apoptosis. However, other sphingolipids, such as S1P, play the opposite role, which induces cancer cell transformation, migration and growth and promotes drug resistance. There are also other sphingolipids, as well as enzymes, played potentially critical roles in cancer physiology and therapeutics. This review aimed to explore the important roles of sphingolipid metabolism in cancer. In this article, we summarized the role and value of sphingolipid metabolism in cancer, including the distribution of sphingolipids, the functions, and their relevance to cancer diagnosis and prognosis. We also summarized the known and potential antitumor targets present in sphingolipid metabolism, analyzed the correlation between sphingolipid metabolism and tumor immunity, and summarize the antitumor effects of natural compounds based on sphingolipids. Through the analysis and summary of sphingolipid antitumor therapeutic targets and immune correlation, we aim to provide ideas for the development of new antitumor drugs, exploration of new therapeutic means for tumors, and study of immunotherapy resistance mechanisms.

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Implication of Ceramide Kinase/C1P in Cancer Development and Progression

Cited by 17 publications

References 108 publications

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

Inhibition of Ceramide Kinase Is Effective against Cisplatin-Resistant Ovarian Cancer Cells by Regulating Ceramide and C1P Levels

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

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