Review Article

Targeting Triglyceride Metabolism for Colorectal Cancer Prevention and Therapy

Author(s): Nagendra Yarla, Venkateshwar Madka and Chinthalapally Rao*

Volume 23, Issue 6, 2022

Published on: 24 August, 2021

Page: [628 - 635] Pages: 8

DOI: 10.2174/1389450122666210824150012


Background: Triglycerides (TG) are one of the major constituents of body fat and energy reservoir, which consist of an ester derived from glycerol and three free fatty acids. TG lipase, monoacylglycerol lipase, fatty acid synthase, and HMG-CoA reductase are some of the key enzymes related to TG metabolism, and their roles in colorectal cancer (CRC) initiation and progression are under investigation.

Methods: The literature search was performed based on various published papers, mostly on triglyceride metabolism relevant to CRC in PubMed, Google Scholar and other search engines. The gene expression profiling of some of the TG metabolic pathway mediators was performed by transcriptomic and/or proteomic data from The Cancer Genome Atlas (TCGA) database using R program and cBioportal software.

Results and Discussion: Accumulating pieces of evidence suggest that TG profiling may be used as a biomarker for the diagnosis and/or prognosis of CRC. Dysregulation of TG metabolism is associated with the initiation and progression of CRC. Most of the TG anabolic pathway mediators are overexpressed and/or overactivated during CRC tumorigenesis, while most TG catabolic pathway mediators are downregulated and/or inactivated based on literature search and correlated with TCGA data. Metabolic enzymes of TG and FAs metabolic pathways are involved in CRC tumor growth survival and metastasis.

Conclusion: Overall studies from the previous literature and our TCGA data analysis demonstrated that the area of research on TG-associated lipid metabolic pathways holds great promise and warranted detailed investigations in this area for the implementation of novel preventive and therapeutic strategies against CRC.

Keywords: Triglyceride metabolism, colorectal cancer, metabolic enzymes, chemoprevention, drug targets, triglycerides.

Graphical Abstract
Statistics C. Published early online January 12, 2021 in CA Cancer Journal for Clinicians First author Rebecca L Siegel, MPH, American Cancer Society, Atlanta, Ga; Cancer Facts & Figures 2021. Atlanta, Ga: American Cancer Society 2021.
Ahmed S, Shah P, Ahmed O. Biochemistry, Lipids. In: StatPearls. Treasure Island, FL: StatPearls Publishing 2020.
Zewinger S, Reiser J, Jankowski V, et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat Immunol 2020; 21(1): 30-41.
[] [PMID: 31819254]
Chen XQ, Wu PW, Liu DH, Yan SJ, Shen XM, Yang LY. Prognostic significance of high triglyceride and apolipoprotein B levels in patients with stage III and high-risk stage II colorectal cancer undergoing curative surgery. Oncol Lett 2020; 20(1): 705-14.
[] [PMID: 32565996]
Xie C, Wen P, Su J, et al. Elevated serum triglyceride and low-density lipoprotein cholesterol promotes the formation of colorectal polyps. BMC Gastroenterol 2019; 19(1): 195.
[] [PMID: 31752704]
Kim M, Park K. Dietary fat intake and risk of colorectal cancer: A systematic review and meta-analysis of prospective studies. Nutrients 2018; 10(12): 1963.
[] [PMID: 30545042]
Reddy BS. Types and amount of dietary fat and colon cancer risk: Prevention by omega-3 fatty acid-rich diets. Environ Health Prev Med 2002; 7(3): 95-102.
[] [PMID: 21432290]
Mika A, Kobiela J, Pakiet A, et al. Preferential uptake of polyunsaturated fatty acids by colorectal cancer cells. Sci Rep 2020; 10(1): 1954.
[] [PMID: 32029824]
Takeuchi K, Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab 2009; 296(6): E1195-209.
[] [PMID: 19336658]
Oh RC, Lanier JB. Management of hypertriglyceridemia. Am Fam Physician 2007; 75(9): 1365-71.
[PMID: 17508532]
Sascău R, Clement A, Radu R, Prisacariu C, Stătescu C. Triglyceride-rich lipoproteins and their remnants as silent promoters of atherosclerotic cardiovascular disease and other metabolic disorders: A review. Nutrients 2021; 13(6): 1774.
[] [PMID: 34067469]
Kuramoto K, Yamamoto M, Suzuki S, et al. Inhibition of the lipid droplet-peroxisome proliferator-activated receptor α axis suppresses cancer stem cell properties. Genes (Basel) 2021; 12(1): 99.
[] [PMID: 33466690]
Kearney KE, Pretlow TG, Pretlow TP. Increased expression of fatty acid synthase in human aberrant crypt foci: Possible target for colorectal cancer prevention. Int J Cancer 2009; 125(1): 249-52.
[] [PMID: 19358283]
Liu T, Peng F, Yu J, et al. LC-MS-based lipid profile in colorectal cancer patients: TAGs are the main disturbed lipid markers of colorectal cancer progression. Anal Bioanal Chem 2019; 411(20): 5079-88.
[] [PMID: 31201454]
McKeown-Eyssen G. Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 1994; 3(8): 687-95.
[PMID: 7881343]
Hong TT, Shen D, Chen XP, Wu XH, Hua D. Preoperative serum lipid profile and outcome in nonmetastatic colorectal cancer. Chronic Dis Transl Med 2016; 2(4): 241-9.
[] [PMID: 29063049]
Tabuchi M, Kitayama J, Nagawa H. Hypertriglyceridemia is positively correlated with the development of colorectal tubular adenoma in Japanese men. World J Gastroenterol 2006; 12(8): 1261-4.
[] [PMID: 16534881]
Schreiber R, Xie H, Schweiger M. Of mice and men: The physiological role of adipose triglyceride lipase (ATGL). Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864(6): 880-99.
[] [PMID: 30367950]
Yin H, Li W, Mo L, et al. Adipose triglyceride lipase promotes the proliferation of colorectal cancer cells via enhancing the lipolytic pathway. J Cell Mol Med 2021; 25(8): 3963-75.
[] [PMID: 33621408]
Munechika E, Hiroshi I, Akikazu H, Yusuke M, Ryoko Y, Makoto N. Dysregulated lipid metabolism and lipid accumulation in colorectal neoplasms. J Comprehen Cancer Res 2019; 3(1): 100012.
Zagani R, El-Assaad W, Gamache I, Teodoro JG. Inhibition of adipose triglyceride lipase (ATGL) by the putative tumor suppressor G0S2 or a small molecule inhibitor attenuates the growth of cancer cells. Oncotarget 2015; 6(29): 28282-95.
[] [PMID: 26318046]
Ou J, Miao H, Ma Y, et al. Loss of abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition. Cell Rep 2014; 9(5): 1798-811.
[] [PMID: 25482557]
Wu H, Han Y, Rodriguez Sillke Y, et al. Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol Med 2019; 11(11): e10698.
[] [PMID: 31602788]
Jha P, Claudel T, Baghdasaryan A, et al. Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia. Hepatology 2014; 59(3): 858-69.
[] [PMID: 24002947]
Lettieri Barbato D, Aquilano K, Baldelli S, et al. Proline oxidase-adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation. Cell Death Differ 2014; 21(1): 113-23.
[] [PMID: 24096872]
Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV Jr. Thematic review series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 2008; 49(11): 2283-301.
[] [PMID: 18757836]
Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 1997; 272(43): 27218-23.
[] [PMID: 9341166]
Ye L, Zhang B, Seviour EG, et al. Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer. Cancer Lett 2011; 307(1): 6-17.
[] [PMID: 21543155]
Ma M, Bai J, Ling Y, et al. Monoacylglycerol lipase inhibitor JZL184 regulates apoptosis and migration of colorectal cancer cells. Mol Med Rep 2016; 13(3): 2850-6.
[] [PMID: 26847687]
Pagano E, Borrelli F, Orlando P, et al. Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacol Res 2017; 119: 227-36.
[] [PMID: 28193521]
Agarwal AK, Garg A. Enzymatic activity of the human 1-acylglycerol-3-phosphate-O-acyltransferase isoform 11: Upregulated in breast and cervical cancers. J Lipid Res 2010; 51(8): 2143-52.
[] [PMID: 20363836]
Zhang D, Shi R, Xiang W, et al. The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages. Signal Transduct Target Ther 2020; 5(1): 24.
[] [PMID: 32296017]
Yarla NS, Madka V, Pathuri G, Rao CV. Molecular targets in precision chemoprevention of colorectal cancer: An update from pre-clinical to clinical trials. Int J Mol Sci 2020; 21(24): 9609.
[] [PMID: 33348563]
Notarnicola M, Miccolis A, Tutino V, Lorusso D, Caruso MG. Low levels of lipogenic enzymes in peritumoral adipose tissue of colorectal cancer patients. Lipids 2012; 47(1): 59-63.
[] [PMID: 22090062]
Gong J, Lin Y, Zhang H, et al. Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis 2020; 11(4): 267.
[] [PMID: 32327627]
Lu T, Sun L, Wang Z, Zhang Y, He Z, Xu C. Fatty acid synthase enhances colorectal cancer cell proliferation and metastasis via regulating AMPK/mTOR pathway. OncoTargets Ther 2019; 12: 3339-47.
[] [PMID: 31118685]
Wang H, Xi Q, Wu G. Fatty acid synthase regulates invasion and metastasis of colorectal cancer via Wnt signaling pathway. Cancer Med 2016; 5(7): 1599-606.
[] [PMID: 27139420]
Li JN, Gorospe M, Chrest FJ, et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res 2001; 61(4): 1493-9.
[PMID: 11245456]
Ventura R, Mordec K, Waszczuk J, et al. Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression. EBioMedicine 2015; 2(8): 808-24.
[] [PMID: 26425687]
Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 2010; 17(2): 351-60.
[] [PMID: 20228137]
Ni T, He Z, Dai Y, Yao J, Guo Q, Wei L. Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism. Cell Death Dis 2017; 8(6): e2865.
[] [PMID: 28594405]
ClinicalTrialsgov; ID NCT02980029
Raimondo S, Saieva L, Cristaldi M, Monteleone F, Fontana S, Alessandro R. Label-free quantitative proteomic profiling of colon cancer cells identifies acetyl-CoA carboxylase alpha as antitumor target of Citrus limon-derived nanovesicles. J Proteomics 2018; 173: 1-11.
[] [PMID: 29197582]
Wang C, Xu C, Sun M, Luo D, Liao DF, Cao D. Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. Biochem Biophys Res Commun 2009; 385(3): 302-6.
[] [PMID: 19450551]
Longo J, van Leeuwen JE, Elbaz M, Branchard E, Penn LZ. Statins as Anticancer Agents in the Era of Precision Medicine. Clin Cancer Res 2020; 26(22): 5791-800.
[] [PMID: 32887721]
Clinical trials identification numbers: NCT01011478 2020.
Clinical trials identification numbers: NCT00994903 2020.
Li Y, He X, Ding Y, Chen H, Sun L. Statin uses and mortality in colorectal cancer patients: An updated systematic review and meta-analysis. Cancer Med 2019; 8(6): 3305-13.
[] [PMID: 31069997]
Lochhead P, Chan AT. Statins and colorectal cancer. Clin Gastroenterol Hepatol 2013; 11(2): 109-18.
[] [PMID: 22982096]
Kasim SE, LeBoeuf RC, Khilnani S, Tallapaka L, Dayananda D, Jen KL. Mechanisms of triglyceride-lowering effect of an HMG-CoA reductase inhibitor in a hypertriglyceridemic animal model, the Zucker obese rat. J Lipid Res 1992; 33(1): 1-7.
[] [PMID: 1552226]
Bengtsson E, Nerjovaj P, Wangefjord S, et al. HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome. Diagn Pathol 2014; 9: 78.
[] [PMID: 24708688]
Wei TT, Lin YT, Chen WS, et al. Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer. EBioMedicine 2016; 10: 124-36. [published correction appears in EBioMedicine. 2017 Nov 16;].
[] [PMID: 27448759]
Al-Haidari AA, Syk I, Thorlacius H. HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation. Biochem Biophys Res Commun 2014; 446(1): 68-72.
[] [PMID: 24582560]
Karagkounis G, DeVecchio J, Ferrandon S, Kalady MF. Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surg Endosc 2018; 32(3): 1533-9.
[] [PMID: 28916945]
Suh N, Reddy BS, DeCastro A, et al. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats. Cancer Prev Res (Phila) 2011; 4(11): 1895-902. [Phila].
[] [PMID: 21764859]
Swamy MV, Patlolla JM, Steele VE, Kopelovich L, Reddy BS, Rao CV. Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCMin mice. Cancer Res 2006; 66(14): 7370-7.
[] [PMID: 16849589]
Xiao H, Zhang Q, Lin Y, Reddy BS, Yang CS. Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int J Cancer 2008; 122(9): 2115-24.
[] [PMID: 18172863]
Ohmachi T, Inoue H, Mimori K, et al. Fatty acid binding protein 6 is overexpressed in colorectal cancer. Clin Cancer Res 2006; 12(17): 5090-5.
[] [PMID: 16951225]
Lawrie LC, Dundas SR, Curran S, Murray GI. Liver fatty acid binding protein expression in colorectal neoplasia. Br J Cancer 2004; 90(10): 1955-60.
[] [PMID: 15138477]
Tian W, Zhang W, Zhang Y, et al. FABP4 promotes invasion and metastasis of colon cancer by regulating fatty acid transport. Cancer Cell Int 2020; 20: 512.
[] [PMID: 33088219]
Kawaguchi K, Senga S, Kubota C, Kawamura Y, Ke Y, Fujii H. High expression of Fatty Acid-Binding Protein 5 promotes cell growth and metastatic potential of colorectal cancer cells. FEBS Open Bio 2016; 6(3): 190-9.
[] [PMID: 27047747]
Wood SM, Gill AJ, Brodsky AS, et al. Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway. Mod Pathol 2017; 30(1): 123-33.
[] [PMID: 27687006]
Takasu S, Mutoh M, Takahashi M, Nakagama H. Lipoprotein lipase as a candidate target for cancer prevention/therapy. Biochem Res Int 2012; 2012: 398697.
[] [PMID: 22028972]
Niho N, Mutoh M, Takahashi M, Tsutsumi K, Sugimura T, Wakabayashi K. Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice. Proc Natl Acad Sci USA 2005; 102(8): 2970-4.
[] [PMID: 15710887]
Thompson MP, Cooper ST, Parry BR, Tuckey JA. Increased expression of the mRNA for hormone-sensitive lipase in adipose tissue of cancer patients. Biochim Biophys Acta 1993; 1180(3): 236-42.
[] [PMID: 8422428]
Meana C, García-Rostán G, Peña L, et al. The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis. JCI Insight 2018; 3(18): e97506.
[] [PMID: 30232275]
Marchan R, Büttner B, Lambert J, et al. Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma. Cancer Res 2017; 77(17): 4589-601.
[] [PMID: 28652252]
Pellon-Maison M, Montanaro MA, Lacunza E, et al. Glycerol-3-phosphate acyltranferase-2 behaves as a cancer testis gene and promotes growth and tumorigenicity of the breast cancer MDA-MB-231 cell line. PLoS One 2014; 9(6): e100896.
[] [PMID: 24967918]
Sánchez-Martínez R, Cruz-Gil S, García-Álvarez MS, Reglero G, Ramírez de Molina A. Complementary ACSL isoforms contribute to a non-Warburg advantageous energetic status characterizing invasive colon cancer cells. Sci Rep 2017; 7(1): 11143.
[] [PMID: 28894242]
Zaugg K, Yao Y, Reilly PT, et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev 2011; 25(10): 1041-51.
[] [PMID: 21576264]
Mozolewska P, Duzowska K, Pakiet A, Mika A, ŚledziŃski T. Inhibitors of Fatty Acid Synthesis and Oxidation as Potential Anticancer Agents in Colorectal Cancer Treatment. Anticancer Res 2020; 40(9): 4843-56.
[] [PMID: 32878772]
Wang YN, Zeng ZL, Lu J, et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 2018; 37(46): 6025-40.
[] [PMID: 29995871]

© 2023 Bentham Science Publishers | Privacy Policy