Abstract
Aerobic glycolysis is widely accepted as the glucose metabolism for production of biomass such as nucleotides, amino acids, and fatty acids which underlie the anabolic process of cancer cell proliferation. The epithelial–mesenchymal transition (EMT) is a complex cellular mechanism for invasion and metastatic progression in cancer cells. While Snail-mediated EMT regulated by major oncogenic signaling has been well-studied over the last decade, metabolic reprogramming during the EMT has not. In this work, we emphasize the importance of catabolic metabolism for cancer cell survival during cancer cell EMT. Because specific catabolic processes such as autophage and fatty acid oxidation have been well explained, we mainly focus on the general aspects of energy metabolism promoting cancer cell survival under metabolic stress. We also revisit the role of mitochondria in catabolism as oxidative phosphorylation in cancer has long been underestimated. Considering the highly inefficient process of metastatic progression and profound metabolic stress following matrix detachment of solid cancer, catabolic reprogramming during the EMT may play an important role in overcoming metastatic inefficiency of cancer cells.
Similar content being viewed by others
References
Aft, R.L., F.W. Zhang, and D. Gius. 2002. Evaluation of 2-deoxy-d-glucose as a chemotherapeutic agent: mechanism of cell death. British Journal of Cancer 87(7): 805–812. doi:10.1038/sj.bjc.6600547.
Batlle, E., E. Sancho, C. Franci, D. Dominguez, M. Monfar, J. Baulida, and A. Garcia De Herreros. 2000. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology 2(2): 84–89. doi:10.1038/35000034.
Beach, S., H. Tang, S. Park, A.S. Dhillon, E.T. Keller, W. Kolch, and K.C. Yeung. 2008. Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 27(15): 2243–2248. doi:10.1038/sj.onc.1210860.
Benjamin, D.I., B.F. Cravatt, and D.K. Nomura. 2012. Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metabolism 16(5): 565–577. doi:10.1016/j.cmet.2012.09.013.
Birsoy, K., R. Possemato, F.K. Lorbeer, E.C. Bayraktar, P. Thiru, B. Yucel, T. Wang, W.W. Chen, C.B. Clish, and D.M. Sabatini. 2014. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508(7494): 108–112. doi:10.1038/nature13110.
Buchheit, C.L., K.J. Weigel, and Z.T. Schafer. 2014. Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nature Reviews Cancer 14(9): 632–641. doi:10.1038/nrc3789.
Cano, A., M.A. Perez-Moreno, I. Rodrigo, A. Locascio, M.J. Blanco, M.G. del Barrio, F. Portillo, and M.A. Nieto. 2000. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology 2(2): 76–83. doi:10.1038/35000025.
Carracedo, A., L.C. Cantley, and P.P. Pandolfi. 2013. Cancer metabolism: fatty acid oxidation in the limelight. Nature Reviews Cancer 13(4): 227–232. doi:10.1038/nrc3483.
Carracedo, A., D. Weiss, A.K. Leliaert, M. Bhasin, V.C. de Boer, G. Laurent, A.C. Adams, et al. 2012. A metabolic prosurvival role for PML in breast cancer. The Journal of Clinical Investigation 122(9): 3088–3100. doi:10.1172/JCI62129.
Cha, Y.H., N.H. Kim, C. Park, I. Lee, H.S. Kim, and J.I. Yook. 2012. MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling. Cell Cycle 11(7): 1273–1281. doi:10.4161/cc.19618.
Chambers, A.F., A.C. Groom, and I.C. MacDonald. 2002. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer 2(8): 563–572. doi:10.1038/nrc865.
Cheong, J.H., E.S. Park, J. Liang, J.B. Dennison, D. Tsavachidou, C. Nguyen-Charles, K. Wa Cheng, et al. 2011. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Molecular Cancer Therapeutics 10(12): 2350–2362. doi:10.1158/1535-7163.MCT-11-0497.
Christofk, H.R., M.G. Vander Heiden, M.H. Harris, A. Ramanathan, R.E. Gerszten, R. Wei, M.D. Fleming, S.L. Schreiber, and L.C. Cantley. 2008. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184): 230–233. doi:10.1038/nature06734.
Crighton, D., S. Wilkinson, J. O’Prey, N. Syed, P. Smith, P.R. Harrison, M. Gasco, O. Garrone, T. Crook, and K.M. Ryan. 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126(1): 121–134. doi:10.1016/j.cell.2006.05.034.
Cully, M., H. You, A.J. Levine, and T.W. Mak. 2006. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Reviews Cancer 6(3): 184–192. doi:10.1038/nrc1819.
DeBerardinis, R.J., A. Mancuso, E. Daikhin, I. Nissim, M. Yudkoff, S. Wehrli, and C.B. Thompson. 2007. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. The Proceedings of the National Academy of Sciences USA 104(49): 19345–19350. doi:10.1073/pnas.0709747104.
Decensi, A., M. Puntoni, P. Goodwin, M. Cazzaniga, A. Gennari, B. Bonanni, and S. Gandini. 2010. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prevention Research (Phila) 3(11): 1451–1461. doi:10.1158/1940-6207.CAPR-10-0157.
DeVita Jr., V.T., and E. Chu. 2008. A history of cancer chemotherapy. Cancer Research 68(21): 8643–8653. doi:10.1158/0008-5472.CAN-07-6611.
El-Mir, M.Y., V. Nogueira, E. Fontaine, N. Averet, M. Rigoulet, and X. Leverve. 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. Journal of Biological Chemistry 275(1): 223–228.
Escriva, M., S. Peiro, N. Herranz, P. Villagrasa, N. Dave, B. Montserrat-Sentis, S.A. Murray, et al. 2008. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Molecular and Cellular Biology 28(5): 1528–1540. doi:10.1128/MCB.02061-07.
Evans, J.M., L.A. Donnelly, A.M. Emslie-Smith, D.R. Alessi, and A.D. Morris. 2005. Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503): 1304–1305. doi:10.1136/bmj.38415.708634.F7.
Fan, J., J. Ye, J.J. Kamphorst, T. Shlomi, C.B. Thompson, and J.D. Rabinowitz. 2014. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510(7504): 298–302. doi:10.1038/nature13236.
Feng, Z., H. Zhang, A.J. Levine, and S. Jin. 2005. The coordinate regulation of the p53 and mTOR pathways in cells. The Proceedings of the National Academy of Sciences USA 102(23): 8204–8209. doi:10.1073/pnas.0502857102.
Frisch, S.M., and R.A. Screaton. 2001. Anoikis mechanisms. Current Opinion in Cell Biology 13(5): 555–562.
Fung, C., R. Lock, S. Gao, E. Salas, and J. Debnath. 2008. Induction of autophagy during extracellular matrix detachment promotes cell survival. Molecular Biology of the Cell 19(3): 797–806. doi:10.1091/mbc.E07-10-1092.
Gupta, P.B., T.T. Onder, G. Jiang, K. Tao, C. Kuperwasser, R.A. Weinberg, and E.S. Lander. 2009. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138(4): 645–659. doi:10.1016/j.cell.2009.06.034.
Hadad, S., T. Iwamoto, L. Jordan, C. Purdie, S. Bray, L. Baker, G. Jellema, et al. 2011. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Research and Treatment 128(3): 783–794. doi:10.1007/s10549-011-1612-1.
Hardie, D.G., and D.R. Alessi. 2013. LKB1 and AMPK and the cancer-metabolism link—ten years after. BMC Biology 11: 36. doi:10.1186/1741-7007-11-36.
Hitosugi, T., L. Zhou, S. Elf, J. Fan, H.B. Kang, J.H. Seo, C. Shan, et al. 2012. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22(5): 585–600. doi:10.1016/j.ccr.2012.09.020.
Hosono, K., H. Endo, H. Takahashi, M. Sugiyama, E. Sakai, T. Uchiyama, K. Suzuki, et al. 2010. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prevention Research (Phila) 3(9): 1077–1083. doi:10.1158/1940-6207.CAPR-10-0186.
Ito, K., A. Carracedo, D. Weiss, F. Arai, U. Ala, D.E. Avigan, Z.T. Schafer, et al. 2012. A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Medicine 18(9): 1350–1358. doi:10.1038/nm.2882.
Jeon, S.M., N.S. Chandel, and N. Hay. 2012. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485(7400): 661–665. doi:10.1038/nature11066.
Jerby, L., L. Wolf, C. Denkert, G.Y. Stein, M. Hilvo, M. Oresic, T. Geiger, and E. Ruppin. 2012. Metabolic associations of reduced proliferation and oxidative stress in advanced breast cancer. Cancer Research 72(22): 5712–5720. doi:10.1158/0008-5472.CAN-12-2215.
Johnston, S.E., J. Gratten, C. Berenos, J.G. Pilkington, T.H. Clutton-Brock, J.M. Pemberton, and J. Slate. 2013. Life history trade-offs at a single locus maintain sexually selected genetic variation. Nature 502(7469): 93–95. doi:10.1038/nature12489.
Kim, N.H., Y.H. Cha, S.E. Kang, Y. Lee, I. Lee, S.Y. Cha, J.K. Ryu, et al. 2013. p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells. Cell Cycle 12(10): 1578–1587. doi:10.4161/cc.24739.
Kim, N.H., H.S. Kim, N.G. Kim, I. Lee, H.S. Choi, X.Y. Li, S.E. Kang, et al. 2011a. p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal 4(197): ra71. doi:10.1126/scisignal.2001744.
Kim, N.H., H.S. Kim, X.Y. Li, I. Lee, H.S. Choi, S.E. Kang, S.Y. Cha, et al. 2011b. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition. Journal of Cell Biology 195(3): 417–433. doi:10.1083/jcb.201103097.
Koppenol, W.H., P.L. Bounds, and C.V. Dang. 2011. Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Reviews Cancer 11(5): 325–337. doi:10.1038/nrc3038.
Kottakis, F., and N. Bardeesy. 2012. LKB1-AMPK axis revisited. Cell Research 22(12): 1617–1620. doi:10.1038/cr.2012.108.
LeBleu, V.S., J.T. O’Connell, K.N. Gonzalez Herrera, H. Wikman, K. Pantel, M.C. Haigis, F.M. de Carvalho, et al. 2014. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature Cell Biology 16(10): 992–1003. doi:10.1038/ncb3039.
Locasale, J.W., A.R. Grassian, T. Melman, C.A. Lyssiotis, K.R. Mattaini, A.J. Bass, G. Heffron, et al. 2011. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics 43(9): 869–874. doi:10.1038/ng.890.
Luzzi, K.J., I.C. MacDonald, E.E. Schmidt, N. Kerkvliet, V.L. Morris, A.F. Chambers, and A.C. Groom. 1998. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology 153(3): 865–873. doi:10.1016/S0002-9440(10)65628-3.
Madiraju, A.K., D.M. Erion, Y. Rahimi, X.M. Zhang, D.T. Braddock, R.A. Albright, B.J. Prigaro, et al. 2014. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510(7506): 542–546. doi:10.1038/nature13270.
Mani, S.A., W. Guo, M.J. Liao, E.N. Eaton, A. Ayyanan, A.Y. Zhou, M. Brooks, et al. 2008. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133(4): 704–715. doi:10.1016/j.cell.2008.03.027.
Mathew, R., S. Kongara, B. Beaudoin, C.M. Karp, K. Bray, K. Degenhardt, G. Chen, S. Jin, and E. White. 2007. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes & Development 21(11): 1367–1381. doi:10.1101/gad.1545107.
Menendez, J.A., and R. Lupu. 2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Reviews Cancer 7(10): 763–777. doi:10.1038/nrc2222.
Mills, K.R., M. Reginato, J. Debnath, B. Queenan, and J.S. Brugge. 2004. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. The Proceedings of the National Academy of Sciences USA 101(10): 3438–3443. doi:10.1073/pnas.0400443101.
Mizushima, N., B. Levine, A.M. Cuervo, and D.J. Klionsky. 2008. Autophagy fights disease through cellular self-digestion. Nature 451(7182): 1069–1075. doi:10.1038/nature06639.
Ni Chonghaile, T., K.A. Sarosiek, T.T. Vo, J.A. Ryan, A. Tammareddi, G. Moore Vdel, J. Deng, et al. 2011. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334(6059): 1129–1133. doi:10.1126/science.1206727.
Niraula, S., R.J. Dowling, M. Ennis, M.C. Chang, S.J. Done, N. Hood, J. Escallon, et al. 2012. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Research and Treatment 135(3): 821–830. doi:10.1007/s10549-012-2223-1.
Owen, M.R., E. Doran, and A.P. Halestrap. 2000. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal 348(Pt 3): 607–614.
Pollak, M.N. 2012. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2(9): 778–790. doi:10.1158/2159-8290.CD-12-0263.
Rhim, A.D., E.T. Mirek, N.M. Aiello, A. Maitra, J.M. Bailey, F. McAllister, M. Reichert, et al. 2012. EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2): 349–361. doi:10.1016/j.cell.2011.11.025.
Schafer, Z.T., A.R. Grassian, L. Song, Z. Jiang, Z. Gerhart-Hines, H.Y. Irie, S. Gao, P. Puigserver, and J.S. Brugge. 2009. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461(7260): 109–113. doi:10.1038/nature08268.
Schwartz, R.A., G. Fernandez, K. Kotulska, and S. Jozwiak. 2007. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. Journal of the American Academy of Dermatology 57(2): 189–202. doi:10.1016/j.jaad.2007.05.004.
Singh, R., and A.M. Cuervo. 2012. Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol 2012: 282041. doi:10.1155/2012/282041.
Tarin, D., J.E. Price, M.G. Kettlewell, R.G. Souter, A.C. Vass, and B. Crossley. 1984. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Research 44(8): 3584–3592.
Vander Heiden, M.G., L.C. Cantley, and C.B. Thompson. 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930): 1029–1033. doi:10.1126/science.1160809.
Vander Heiden, M.G., J.W. Locasale, K.D. Swanson, H. Sharfi, G.J. Heffron, D. Amador-Noguez, H.R. Christofk, et al. 2010. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329(5998): 1492–1499. doi:10.1126/science.1188015.
Vega, S., A.V. Morales, O.H. Ocana, F. Valdes, I. Fabregat, and M.A. Nieto. 2004. Snail blocks the cell cycle and confers resistance to cell death. Genes & Development 18(10): 1131–1143. doi:10.1101/gad.294104.
Warburg, O. 1956. On the origin of cancer cells. Science 123(3191): 309–314.
Ward, P.S., and C.B. Thompson. 2012. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21(3): 297–308. doi:10.1016/j.ccr.2012.02.014.
Wheaton, W.W., S.E. Weinberg, R.B. Hamanaka, S. Soberanes, L.B. Sullivan, E. Anso, A. Glasauer, et al. 2014. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3: e02242. doi:10.7554/eLife.02242.
Wise, D.R., and C.B. Thompson. 2010. Glutamine addiction: a new therapeutic target in cancer. Trends in Biochemical Sciences 35(8): 427–433. doi:10.1016/j.tibs.2010.05.003.
Wu, Z.Q., X.Y. Li, C.Y. Hu, M. Ford, C.G. Kleer, and S.J. Weiss. 2012. Canonical Wnt signaling regulates Slug activity and links epithelial–mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. The Proceedings of the National Academy of Sciences USA 109(41): 16654–16659. doi:10.1073/pnas.1205822109.
Yang, Z., and D.J. Klionsky. 2010. Mammalian autophagy: core molecular machinery and signaling regulation. Current Opinion in Cell Biology 22(2): 124–131. doi:10.1016/j.ceb.2009.11.014.
Yook, J.I., X.Y. Li, I. Ota, E.R. Fearon, and S.J. Weiss. 2005. Wnt-dependent regulation of the E-cadherin repressor snail. Journal of Biological Chemistry 280(12): 11740–11748. doi:10.1074/jbc.M413878200.
Yook, J.I., X.Y. Li, I. Ota, C. Hu, H.S. Kim, N.H. Kim, S.Y. Cha, et al. 2006. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nature Cell Biology 8(12): 1398–1406. doi:10.1038/ncb1508.
Acknowledgments
We thank E. Tunkle for preparation of the manuscript. This work was supported by grants from the National Research Foundation of Korea (NRF-2012M3A9B2052523, NRF-2013R1A1A1011652, NRF-2014R1A2A1A05004670, NRF-2014R1A6A3A04055110), and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1420310).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Cha, Y.H., Yook, J.I., Kim, H.S. et al. Catabolic metabolism during cancer EMT. Arch. Pharm. Res. 38, 313–320 (2015). https://doi.org/10.1007/s12272-015-0567-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-015-0567-x