Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.
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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Cook AD, Single R, McCahill LE. Surgical resection of primary tumors in patients who present with stage IV colorectal cancer: an analysis of surveillance, epidemiology, and end results data, 1988 to 2000. Ann Surg Oncol. 2005;12:637–45.
Pollack LA, Gotway CA, Bates JH, Parikh-Patel A, Richards TB, Seeff LC, et al. Use of the spatial scan statistic to identify geographic variations in late stage colorectal cancer in California (United States). Cancer Causes Control. 2006;17:449–57.
Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature. 2016;529:298–306.
Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP. TGF-beta upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest. 2013;123:150–63.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235–9.
Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA. 2000;97:14608–13.
Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62.
Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5:816–26.
Yawata A, Adachi M, Okuda H, Naishiro Y, Takamura T, Hareyama M, et al. Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene. 1998;16:2681–6.
Streuli CH, Gilmore AP. Adhesion-mediated signaling in the regulation of mammary epithelial cell survival. J Mammary Gland Biol Neoplasia. 1999;4:183–91.
Houten SM, Wanders RJ. A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 2010;33:469–77.
Houten SM, Violante S, Ventura FV, Wanders RJ. The biochemistry and physiology of mitochondrial fatty acid beta-oxidation and its genetic disorders. Annu Rev Physiol. 2016;78:23–44.
Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9.
Harjes U, Kalucka J, Carmeliet P. Targeting fatty acid metabolism in cancer and endothelial cells. Crit Rev Oncol Hematol. 2016;97:15–21.
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503.
Zammit VA. Carnitine palmitoyltransferase 1: central to cell function. IUBMB Life. 2008;60:347–54.
Setoyama D, Fujimura Y, Miura D. Metabolomics reveals that carnitine palmitoyltransferase-1 is a novel target for oxidative inactivation in human cells. Genes Cells. 2013;18:1107–19.
Casals N, Zammit V, Herrero L, Fado R, Rodriguez-Rodriguez R, Serra D. Carnitine palmitoyltransferase 1C: from cognition to cancer. Prog Lipid Res. 2016;61:134–48.
McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997;244:1–14.
Qu Q, Zeng F, Liu X, Wang QJ, Deng F. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis. 2016;7:e2226.
Gatza ML, Silva GO, Parker JS, Fan C, Perou CM. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat Genet. 2014;46:1051–9.
Ricciardi MR, Mirabilii S, Allegretti M, Licchetta R, Calarco A, Torrisi MR, et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood. 2015;126:1925–9.
Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L, et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther. 2014;13:2361–71.
Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature. 2009;461:109–13.
Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485:661–5.
Zhu L, Ploessl K, Zhou R, Mankoff D, Kung HF. Metabolic imaging of glutamine in cancer. J Nucl Med. 2017;58:533–7.
Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994;124:619–26.
Giancotti FG, Ruoslahti E. Integrin signaling. Science. 1999;285:1028–32.
Aslan B, Monroig P, Hsu MC, Pena GA, Rodriguez-Aguayo C, Gonzalez-Villasana V, et al. The ZNF304-integrin axis protects against anoikis in cancer. Nat Commun. 2015;6:7351.
Schackmann RC, van Amersfoort M, Haarhuis JH, Vlug EJ, Halim VA, Roodhart JM, et al. Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance. J Clin Invest. 2011;121:3176–88.
Strilic B, Offermanns S. Intravascular survival and extravasation of tumor cells. Cancer Cell. 2017;32:282–93.
Buchheit CL, Weigel KJ, Schafer ZT. Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nat Rev Cancer. 2014;14:632–41.
Noguchi T, Toiyama Y, Kitajima T, Imaoka H, Hiro J, Saigusa S, et al. miRNA-503 promotes tumor progression and is associated with early recurrence and poor prognosis in human colorectal cancer. Oncology. 2016;90:221–31.
Okugawa Y, Toiyama Y, Toden S, Mitoma H, Nagasaka T, Tanaka K, et al. Clinical significance of SNORA42 as an oncogene and a prognostic biomarker in colorectal cancer. Gut. 2017;66:107–17.
D’Amato NC, Rogers TJ, Gordon MA, Greene LI, Cochrane DR, Spoelstra NS, et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 2015;75:4651–64.
Jin L, Chun J, Pan C, Alesi GN, Li D, Magliocca KR, et al. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene. 2017;36:3797–806.
Rodrigues MF, Obre E, de Melo FH, Santos GC Jr, Galina A, Jasiulionis MG, et al. Enhanced OXPHOS, glutaminolysis and beta-oxidation constitute the metastatic phenotype of melanoma cells. Biochem J. 2016;473:703–15.
Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541:41–5.
Paumen MB, Ishida Y, Han H, Muramatsu M, Eguchi Y, Tsujimoto Y, et al. Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. Biochem Biophys Res Commun. 1997;231:523–5.
Giordano A, Calvani M, Petillo O, Grippo P, Tuccillo F, Melone MA, et al. tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1. Cell Death Differ. 2005;12:603–13.
Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8:579–91.
Cully M. Anticancer drugs: cutting the antioxidant supply chain. Nat Rev Drug Discov. 2016;16:15.
Ju HQ, Lu YX, Wu QN, Liu J, Zeng ZL, Mo HY, et al. Disrupting G6PD-mediated redox homeostasis enhances chemosensitivity in colorectal cancer. Oncogene. 2017;36:6282–92.
Dey S, Sayers CM, Verginadis II, Lehman SL, Cheng Y, Cerniglia GJ, et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest. 2015;125:2592–608.
Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, et al. Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell. 2011;19:401–15.
Hernlund E, Ihrlund LS, Khan O, Ates YO, Linder S, Panaretakis T, et al. Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int J Cancer. 2008;123:476–83.
Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010;120:142–56.
Pacilli A, Calienni M, Margarucci S, D’Apolito M, Petillo O, Rocchi L, et al. Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis. J Natl Cancer Inst. 2013;105:489–98.
Hinderling VB, Schrauwen P, Langhans W, Westerterp-Plantenga MS. The effect of etomoxir on 24-h substrate oxidation and satiety in humans. Am J Clin Nutr. 2002;76:141–7.
Cabrero A, Merlos M, Laguna JC, Carrera MV. Down-regulation of acyl-CoA oxidase gene expression and increased NF-kappaB activity in etomoxir-induced cardiac hypertrophy. J Lipid Res. 2003;44:388–98.
Holubarsch CJ, Rohrbach M, Karrasch M, Boehm E, Polonski L, Ponikowski P, et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin Sci (Lond). 2007;113:205–12.
Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14:11–31.
Rufer AC, Thoma R, Hennig M. Structural insight into function and regulation of carnitine palmitoyltransferase. Cell Mol Life Sci. 2009;66:2489–501.
Conti R, Mannucci E, Pessotto P, Tassoni E, Carminati P, Giannessi F, et al. Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis. Diabetes. 2011;60:644–51.
Ju HQ, Lu YX, Chen DL, Tian T, Mo HY, Wei XL, et al. Redox regulation of stem-like cells though the CD44v-xCT axis in colorectal cancer: mechanisms and therapeutic implications. Theranostics. 2016;6:1160–75.
Huang A, Ju HQ, Liu K, Zhan G, Liu D, Wen S, et al. Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation. Cancer Lett. 2016;377:149–57.
This research was supported by the National Natural Science Foundation of China (81602137, 81572392); Natural Science Foundation of Guangdong Province (2017A030313485, 2014A030312015); Science and Technology Program of Guangdong (2015B020232008), Science and Technology Program of Guangzhou (15570006, 201508020250, 201604020003) and by grants from Pearl River S&T Nova Program of Guangzhou (201806010002).
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The authors declare that they have no conflict of interest.
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Wang, Y., Zeng, Z., Lu, J. et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 37, 6025–6040 (2018). https://doi.org/10.1038/s41388-018-0384-z
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