Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence

Huizhen Zhang; Yongtao Wang; Lihuan Guan; Yixin Chen; Panpan Chen; Jiahong Sun; Frank J. Gonzalez; Min Huang; Huichang Bi

doi:10.1016/j.jpha.2020.04.004

Volume 11 Issue 3

Jun. 2021

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Article Navigation > Journal of Pharmaceutical Analysis > 2021 > 11(3): 340-350

Huizhen Zhang, Yongtao Wang, Lihuan Guan, Yixin Chen, Panpan Chen, Jiahong Sun, Frank J. Gonzalez, Min Huang, Huichang Bi. Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence[J]. Journal of Pharmaceutical Analysis, 2021, 11(3): 340-350. doi: 10.1016/j.jpha.2020.04.004

Citation:

Huizhen Zhang, Yongtao Wang, Lihuan Guan, Yixin Chen, Panpan Chen, Jiahong Sun, Frank J. Gonzalez, Min Huang, Huichang Bi. Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence[J]. Journal of Pharmaceutical Analysis, 2021, 11(3): 340-350. doi: 10.1016/j.jpha.2020.04.004

Citation:

Huizhen Zhang, Yongtao Wang, Lihuan Guan, Yixin Chen, Panpan Chen, Jiahong Sun, Frank J. Gonzalez, Min Huang, Huichang Bi. Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence[J]. Journal of Pharmaceutical Analysis, 2021, 11(3): 340-350. doi: 10.1016/j.jpha.2020.04.004

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Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence

doi: 10.1016/j.jpha.2020.04.004

a. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China;
b. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

Funds:

The work was supported by the National Key Research and Development Program of China (Grant No. 2017YFE0109900), the National Natural Science Foundation of China (Grant Nos. 82025034 and 81973392), the Shenzhen Science and Technology Program (Grant No. KQTD20190929174023858), the Natural Science Foundation of Guangdong (Grant No. 2017A030311018), the 111 project (Grant No. B16047), the Key Laboratory Foundation of Guangdong Province (Grant No. 2017B030314030), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. 2017BT01Y093), and the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant No. 2017B090903004).

Received Date: Jan. 09, 2020
Accepted Date: Apr. 15, 2020
Rev Recd Date: Mar. 10, 2020
Available Online: Jan. 24, 2022
Publish Date: Jun. 15, 2021

Abstract

Abstract

Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C (CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1, MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis. Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene mRNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.
- Lipidomics,
- Lipid accumulation,
- Lipid peroxidation,
- Oxidative stress,
- Mitochondrial dysfunction,
- Anticancer target

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References(55)

References

T. Kuilman, C. Michaloglou, W.J. Mooi, et al., The essence of senescence, Genes Dev. 24 (2010) 2463-2479

R. Salama, M. Sadaie, M. Hoare, et al., Cellular senescence and its effector programs, Genes Dev. 28 (2014) 99-114

C. Lopez-Otin, M.A. Blasco, L. Partridge, et al., The hallmarks of aging, Cell 153 (2013) 1194-1217

D. Munoz-Espin, M. Serrano, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Biol. 15 (2014) 482-496

J. Campisi, Aging, cellular senescence, and cancer, Annu. Rev. Physiol. 75 (2013) 685-705

J. Campisi, Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors, Cell 120 (2005) 513-522

D.Y. Lizardo, Y.L. Lin, O. Gokcumen, et al., Regulation of lipids is central to replicative senescence, Mol. Biosyst. 13 (2017) 498-509

A.K. Hauck, D.A. Bernlohr, Oxidative stress and lipotoxicity, J. Lipid Res. 57 (2016) 1976-1986

Y. Lee, H. Hirose, M. Ohneda, et al., Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 10878-10882

J.E. Schaffer, Lipotoxicity: Many roads to cell dysfunction and cell death: Introduction to a thematic review series, J. Lipid Res. 57 (2016) 1327-1328

T.J. Biden, E. Boslem, K.Y. Chu, et al., Lipotoxic endoplasmic reticulum stress, beta cell failure, and type 2 diabetes mellitus, Trends Endocrinol. Metab. 25 (2014) 389-398

T. Bilinski, T. Paszkiewicz, R. Zadrag-Tecza, Energy excess is the main cause of accelerated aging of mammals, Oncotarget 6 (2015) 12909-12919

H. Sies, Oxidative stress: a concept in redox biology and medicine, Redox Biol. 4 (2015) 180-183

P. Schrauwen, V. Schrauwen-Hinderling, J. Hoeks, et al., Mitochondrial dysfunction and lipotoxicity, Biochim. Biophys. Acta 1801 (2010) 266-271

S. Gallage, J. Gil, Mitochondrial dysfunction meets senescence, Trends Biochem. Sci. 41 (2016) 207-209

M. Slawik, A.J. Vidal-Puig, Lipotoxicity, overnutrition and energy metabolism in aging, Ageing Res. Rev. 5 (2006) 144-164

N. Casals, V. Zammit, L. Herrero, et al., Carnitine palmitoyltransferase 1C: From cognition to cancer, Prog. Lipid Res. 61 (2016) 134-148

N.T. Price, F.R. van der Leij, V.N. Jackson, et al., A novel brain-expressed protein related to carnitine palmitoyltransferase I, Genomics 80 (2002) 433-442

M.J. Wolfgang, T. Kurama, Y. Dai, et al., The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 7282-7287

X.F. Gao, W. Chen, X.P. Kong, et al., Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake, Diabetologia 52 (2009) 912-920

P. Carrasco, J. Jacas, I. Sahun, et al., Carnitine palmitoyltransferase 1C deficiency causes motor impairment and hypoactivity, Behav. Brain Res. 256 (2013) 291-297

K. Zaugg, Y. Yao, P.T. Reilly, et al., Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress, Genes Dev. 25 (2011) 1041-1051

N. Sanchez-Macedo, J. Feng, B. Faubert, et al., Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model, Cell Death Differ. 20 (2013) 659-668

Y. Wang, Y. Chen, L. Guan, et al., Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming, Cell Death Differ. 25 (2018) 735-748

Y. Chen, Y. Wang, Y. Huang, et al., PPARalpha regulates tumor cell proliferation and senescence via a novel target gene carnitine palmitoyltransferase 1C, Carcinogenesis 38 (2017) 474-483

L. Guan, Y. Chen, Y. Wang, et al., Effects of carnitine palmitoyltransferases on cancer cellular senescence, J. Cell. Physiol. (2018)

H. Zhang, Y. Gao, J. Sun, et al., Optimization of lipid extraction and analytical protocols for UHPLC-ESI-HRMS-based lipidomic analysis of adherent mammalian cancer cells, Anal. Bioanal. Chem. 409 (2017) 5349-5358

C. Chinopoulos, V. Adam-Vizi, Mitochondria as ATP consumers in cellular pathology, Biochim. Biophys. Acta 1802 (2010) 221-227

J. Campisi, Aging and cancer: the double-edged sword of replicative senescence, J. Am. Geriatr. Soc. 45 (1997) 482-488

Y. Dai, M.J. Wolfgang, S.H. Cha, et al., Localization and effect of ectopic expression of CPT1c in CNS feeding centers, Biochem. Biophys. Res. Commun. 359 (2007) 469-474

N. Price, F. van der Leij, V. Jackson, et al., A novel brain-expressed protein related to carnitine palmitoyltransferase I, Genomics 80 (2002) 433-442

A.Y. Sierra, E. Gratacos, P. Carrasco, et al., CPT1c is localized in endoplasmic reticulum of neurons and has carnitine palmitoyltransferase activity, J. Biol. Chem. 283 (2008) 6878-6885

E. Currie, A. Schulze, R. Zechner, et al., Cellular fatty acid metabolism and cancer, Cell Metab. 18 (2013) 153-161

X. Han, R.W. Gross, Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: a bridge to lipidomics, J. Lipid Res. 44 (2003) 1071-1079

K.J. Williams, J.P. Argus, Y. Zhu, et al., An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity, Cancer Res. 73 (2013) 2850-2862

P.C. Calder, Functional Roles of Fatty Acids and Their Effects on Human Health, JPEN J. Parenter. Enteral Nutr. 39 (2015) 18S-32S

M.J. Wolfgang, S.H. Cha, D.S. Millington, et al., Brain-specific carnitine palmitoyl-transferase-1c: role in CNS fatty acid metabolism, food intake, and body weight, J. Neurochem. 105 (2008) 1550-1559

J.H. Ford, Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging, Age 32 (2010) 231-237

Y. Gong, L.J. Dou, J. Liang, Link between obesity and cancer: role of triglyceride/free fatty acid cycling, Eur. Rev. Med. Pharmacol. Sci. 18 (2014) 2808-2820

C. Rinaldi, T. Schmidt, A.J. Situ, et al., Mutation in CPT1C associated with pure autosomal dominant spastic paraplegia, JAMA Neurol. 72 (2015) 561

E.E. Farmer, M.J. Mueller, ROS-mediated lipid peroxidation and RES-activated signaling, Annu. Rev. Plant Biol. 64 (2013) 429-450

T. Borchert, D. Hubscher, C.I. Guessoum, et al., Catecholamine-dependent β-adrenergic signaling in a pluripotent stem cell model of Takotsubo cardiomyopathy, J. Am. Coll. Cardiol. 70 (2017) 975-991

J. Lee, M.J. Wolfgang, Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism, BMC Biochem. 13 (2012) 23

M. Schlame, M.L. Greenberg, Biosynthesis, remodeling and turnover of mitochondrial cardiolipin, Biochim. Biophys. Acta 1862 (2017) 3-7

J.P. Monteiro, P.J. Oliveira, A.S. Jurado, Mitochondrial membrane lipid remodeling in pathophysiology: a new target for diet and therapeutic interventions, Prog. Lipid Res. 52 (2013) 513-528

M.A. Kiebish, X. Han, H. Cheng, et al., Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer, J. Lipid Res. 49 (2008) 2545-2556

S. Chen, Q. Fan, A. Li, et al., Dynamic mobilization of PGC-1alpha mediates mitochondrial biogenesis for the protection of RGC-5 cells by resveratrol during serum deprivation, Apoptosis 18 (2013) 786-799

M. Hildenbeutel, E.L. Hegg, K. Stephan, et al., Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondrial translation, J. Cell Biol. 205 (2014) 511-524

F. Gibellini, T.K. Smith, The Kennedy pathway--De novo synthesis of phosphatidylethanolamine and phosphatidylcholine, IUBMB life 62 (2010) 414-428

V.A. Fajardo, L. McMeekin, P.J. LeBlanc, Influence of phospholipid species on membrane fluidity: a meta-analysis for a novel phospholipid fluidity index, J. Membr. Biol. 244 (2011) 97-103

K. Bienias, A. Fiedorowicz, A. Sadowska, et al., Regulation of sphingomyelin metabolism, Pharmacol. Rep. 68 (2016) 570-581

M.M. Mielke, V.V. Bandaru, D. Han, et al., Factors affecting longitudinal trajectories of plasma sphingomyelins: the Baltimore Longitudinal Study of Aging, Aging cell 14 (2015) 112-121

P. Carrasco, I. Sahun, J. McDonald, et al., Ceramide levels regulated by carnitine palmitoyltransferase 1C control dendritic spine maturation and cognition, J. Biol. Chem. 287 (2012) 21224-21232

Z.X. Meng, Y. Yin, J.H. Lv, et al., Aberrant activation of liver X receptors impairs pancreatic beta cell function through upregulation of sterol regulatory element-binding protein 1c in mouse islets and rodent cell lines, Diabetologia 55 (2012) 1733-1744

L. He, T. Kim, Q. Long, et al., Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity, Circulation 126 (2012) 1705-1716

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