Metabolic Flux Analysis Reveals the Roles of Stearate and Oleate on CPT1C-mediated Tumor Cell Senescence

Cellular senescence is a state of proliferative arrest, and the development of carcinoma can be suppressed by conferring tumor cell senescence. Recently, we found that carnitine palmitoyltransferase 1C (CPT1C) controls tumor cell proliferation and senescence via regulating lipid metabolism and mitochondrial function. Here, 13C-metabolic flux analysis (13C-MFA) was performed and the results revealed that CPT1C knockdown in MDA-MB-231 cells significantly induced cellular senescence accompanied by altered fatty acid metabolism. Strikingly, stearate synthesis was decreased while oleate was increased. Furthermore, stearate significantly inhibited proliferation while oleate reversed the senescent phenotype induced by silencing CPT1C in MDA-MB-231 cells as well as PANC-1 cells. A939572, an inhibitor of stearoyl-Coenzyme A desaturase 1, had the same effect as stearate to inhibit cellular proliferation. These results demonstrated that stearate and oleate are involved in CPT1C-mediated tumor cellular senescence, and the regulation of stearate/oleate rate via inhibition of SCD-1 could be an additional strategy with depletion of CPT1C for cancer therapy.

[1]  Chi-Hong Chao,et al.  Mutant p53-microRNA-200c-ZEB2-Axis-Induced CPT1C Elevation Contributes to Metabolic Reprogramming and Tumor Progression in Basal-Like Breast Cancers , 2022, Frontiers in Oncology.

[2]  Yu Zhang,et al.  CPT1C promotes the potential of gastric cancer ovarian metastasis through up-regulating fatty acid oxidation , 2022, Acta biochimica et biophysica Sinica.

[3]  Q. Ye,et al.  MicroRNA-377-3p inhibits hepatocellular carcinoma growth and metastasis through negative regulation of CPT1C-mediated fatty acid oxidation , 2022, Cancer & metabolism.

[4]  Hai Hu,et al.  Enhanced fatty acid oxidation mediated by CPT1C promotes gastric cancer progression. , 2020, Journal of gastrointestinal oncology.

[5]  M. Huang,et al.  Carnitine palmitoyltransferase 1C reverses cellular senescence of MRC‐5 fibroblasts via regulating lipid accumulation and mitochondrial function , 2020, Journal of cellular physiology.

[6]  F. Gonzalez,et al.  A novel miR-1291-ERRα-CPT1C axis modulates tumor cell proliferation, metabolism and tumorigenesis , 2020, Theranostics.

[7]  F. Gonzalez,et al.  Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence , 2020, Journal of pharmaceutical analysis.

[8]  Peng Huang,et al.  Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence , 2020, Aging.

[9]  J. Li,et al.  Effects of ME3 on the proliferation, invasion and metastasis of pancreatic cancer cells through epithelial-mesenchymal transition. , 2019, Neoplasma.

[10]  Prashant Mishra,et al.  Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. , 2019, Cell metabolism.

[11]  A. Scorilas,et al.  Molecular characterization, genomic structure and expression analysis of a gene (CATL1/CPT1C) encoding a third member of the human carnitine acyltransferase family. , 2019, Genomics.

[12]  Seongju Lee,et al.  Cellular senescence: a promising strategy for cancer therapy , 2019, BMB reports.

[13]  Chenfang Dong,et al.  ME1 promotes basal-like breast cancer progression and associates with poor prognosis , 2018, Scientific Reports.

[14]  Z. Selamoğlu,et al.  Malic enzyme 2 as a potential therapeutic drug target for cancer , 2018, IUBMB life.

[15]  M. Huang,et al.  Effects of carnitine palmitoyltransferases on cancer cellular senescence , 2018, Journal of cellular physiology.

[16]  P. Oefner,et al.  Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo. , 2018, Cancer research.

[17]  Peng Huang,et al.  Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming , 2018, Cell Death & Differentiation.

[18]  P. Stacpoole.  Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer , 2017, Journal of the National Cancer Institute.

[19]  Dongwei Su,et al.  Cpt1c regulated by AMPK promotes papillary thyroid carcinomas cells survival under metabolic stress conditions , 2017, Journal of Cancer.

[20]  Chuang Chen,et al.  Autophagy mediates free fatty acid effects on MDA-MB-231 cell proliferation, migration and invasion , 2017, Oncology letters.

[21]  Z. Husain,et al.  Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway , 2017, Scientific Reports.

[22]  Caroline H. Johnson,et al.  PPAR&agr; regulates tumor cell proliferation and senescence via a novel target gene carnitine palmitoyltransferase 1C , 2017, Carcinogenesis.

[23]  C. Burant,et al.  Mass spectrometry analysis shows the biosynthetic pathways supported by pyruvate carboxylase in highly invasive breast cancer cells. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[24]  Christian M. Metallo,et al.  Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions. , 2016, Cell reports.

[25]  Christina Chan,et al.  Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers , 2016, Scientific Reports.

[26]  L. Galluzzi,et al.  Metabolomic analyses reveal that anti-aging metabolites are depleted by palmitate but increased by oleate in vivo , 2015, Cell cycle.

[27]  J. Wallace,et al.  Pyruvate Carboxylase Is Up-Regulated in Breast Cancer and Essential to Support Growth and Invasion of MDA-MB-231 Cells , 2015, PloS one.

[28]  W. Shen,et al.  SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway. , 2015, Cancer letters.

[29]  Koji Yoshimoto,et al.  Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas , 2014, Neuropathology : official journal of the Japanese Society of Neuropathology.

[30]  U. Galderisi,et al.  High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism , 2014, Cancer biology & therapy.

[31]  T. Śledziński,et al.  Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. , 2014, World journal of gastroenterology.

[32]  Robert V Farese,et al.  Cellular fatty acid metabolism and cancer. , 2013, Cell metabolism.

[33]  J. Copland,et al.  Stearoyl-CoA Desaturase 1 Is a Novel Molecular Therapeutic Target for Clear Cell Renal Cell Carcinoma , 2013, Clinical Cancer Research.

[34]  B. Faubert,et al.  Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model , 2013, Cell Death and Differentiation.

[35]  K. Wellen,et al.  Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence , 2012, Nature.

[36]  T. Mak,et al.  Molecular Pathways Molecular Pathways : Tumor Cells Co-opt the Brain-Speci fi c Metabolism Gene CPT 1 C to Promote Survival , 2012 .

[37]  A. Žák,et al.  Fatty acids as biocompounds: their role in human metabolism, health and disease--a review. Part 1: classification, dietary sources and biological functions. , 2011, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[38]  B. Faubert,et al.  Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. , 2011, Genes & development.

[39]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[40]  David F Jarrard,et al.  Therapy-induced senescence in cancer. , 2010, Journal of the National Cancer Institute.

[41]  S. Culine,et al.  Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice , 2010, Molecular Cancer Therapeutics.

[42]  Heinrich Taegtmeyer,et al.  Substrate–Enzyme Competition Attenuates Upregulated Anaplerotic Flux Through Malic Enzyme in Hypertrophied Rat Heart and Restores Triacylglyceride Content: Attenuating Upregulated Anaplerosis in Hypertrophy , 2009, Circulation research.

[43]  G. Shulman,et al.  Brain‐specific carnitine palmitoyl‐transferase‐1c: role in CNS fatty acid metabolism, food intake, and body weight , 2008, Journal of neurochemistry.

[44]  S. Stewart,et al.  Senescence: the good the bad and the dysfunctional. , 2008, Current opinion in genetics & development.

[45]  T. Shimokawa,et al.  The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Prentki,et al.  Oleate Promotes the Proliferation of Breast Cancer Cells via the G Protein-coupled Receptor GPR40* , 2005, Journal of Biological Chemistry.

[47]  Robert V Farese,et al.  Triglyceride accumulation protects against fatty acid-induced lipotoxicity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Nigel Price,et al.  A novel brain-expressed protein related to carnitine palmitoyltransferase I. , 2002, Genomics.

[49]  M. Prentki,et al.  Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. , 2000, Cancer research.

[50]  L. Hayflick.  THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. , 1965, Experimental cell research.

[51]  L. Hayflick,et al.  The serial cultivation of human diploid cell strains. , 1961, Experimental cell research.

[52]  Huafeng Zhang,et al.  Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression , 2015, Cellular and Molecular Life Sciences.

[53]  Funda Meric-Bernstam,et al.  High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients , 2012, Breast Cancer Research and Treatment.