Is heme biosynthesis influenced the mitochondrial function and cell proliferation in cancer?
Abstract
Heme is a compound consisting of an iron (Fe) atom bound to a pyrrole ring forming protoporphyrin IX (PPIX). Protoporphyrin combines with a protein-forming hemoprotein compound that plays an essential role in oxygen-binding and transport as well as in the process of energy production in the mitochondria. Some cancer cells have more heme biosynthesis than normal cells, which is thought to be linked to more cancer cell growth. Inhibition of heme biosynthesis in some cancer cells leads to decreased cell proliferation. This review article discusses the synthesis of heme, the role of heme in energy metabolism, which is needed for cell proliferation, the inhibition of heme synthesis and its effect on cancer cell proliferation, and the possibility of the inhibition of heme biosynthesis as an approach in therapy of cancer in the future.
References
Ye W, Zhang L. Heme controls the expression of cell cycle regulators and cell growth in HeLa cells. Biochem Biophys Res Commun. 2004;315(3):546-54. https://doi.org/10.1016/j.bbrc.2004.01.092
Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002;2(5):331-41. https://doi.org/10.1038/nrc795
Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in biochemical sciences. 2016;41(3):211-8. https://doi.org/10.1016/j.tibs.2015.12.001
Kaambre T, Chekulayev V, Shevchuk I, Karu-Varikmaa M, Timohhina N, Tepp K, et al. Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. J Bioenerg Biomembr. 2012;44(5):539-58. https://doi.org/10.1007/s10863-012-9457-9
Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One. 2011;6(9):e24411. https://doi.org/10.1371/journal.pone.0024411
Hooda J, Cadinu D, Alam MM, Shah A, Cao TM, Sullivan LA, et al. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells. PLoS One. 2013;8(5):e63402. https://doi.org/10.1371/journal.pone.0063402
Victor W. Rodwell DAB, Kathleen M. Botham, Peter J. Kennelly, P. Anthony Weil. Biokimia Harper Edisi 30. Miranti Iskandar FS, Huriawati Hartanto, Lydia Agustina, Lydia Inggrid Mandera, Michael, Nikki Sanjaya, Rosemarie Edgina Sadikin, Sienny Agustin, Wulan Adinda Lestari, editor. Jakarta: EGC; 2017. x + 866 p.
Hooda J, Shah A, Zhang L. Heme, an Essential Nutrient from Dietary Proteins, Critically Impacts Diverse Physiological and Pathological Processes. Nutrients. 2014;6(3):1080-102. https://doi.org/10.3390/nu6031080
Ogun AS JN, Valentine M. Biochemistry, Heme Synthesis. Treasure Island (FL): StatPearls Publishing; 2020 [updated 2020 Jul 10; cited 2020 Oct 1. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537329/.
Heinemann IU, Jahn M, Jahn D. The biochemistry of heme biosynthesis. Archives of Biochemistry and Biophysics. 2008;474(2):238-51. https://doi.org/10.1016/j.abb.2008.02.015
Kumari A. Chapter 8 - Heme Synthesis. In: Kumari A, editor. Sweet Biochemistry: Academic Press; 2018. p. 33-6. https://doi.org/10.1016/B978-0-12-814453-4.00008-X
Donegan RK, Moore CM, Hanna DA, Reddi AR. Handling heme: The mechanisms underlying the movement of heme within and between cells. Free Radic Biol Med. 2019;133:88-100. https://doi.org/10.1016/j.freeradbiomed.2018.08.005
Fleming MD, Hamza I. Mitochondrial heme: an exit strategy at last. J Clin Invest. 2012;122(12):4328-30. https://doi.org/10.1172/JCI66607
Li T, Bonkovsky HL, Guo J-t. Structural analysis of heme proteins: implications for design and prediction. BMC Structural Biology. 2011;11(1):13. https://doi.org/10.1186/1472-6807-11-13
Everse J. Heme Proteins. In: Lennarz WJ, Lane MD, editors. Encyclopedia of Biological Chemistry (Second Edition). Waltham: Academic Press; 2013. p. 532-8. https://doi.org/10.1016/B978-0-12-378630-2.00015-3
Freitas TAK, Saito JA, Wan X, Hou S, Alam M. Chapter 7 - Protoglobin and Globin-coupled Sensors. In: Ghosh A, editor. The Smallest Biomolecules: Diatomics and their Interactions with Heme Proteins. Amsterdam: Elsevier; 2008. p. 175-202. https://doi.org/10.1016/B978-044452839-1.50008-5
Hankeln T, Burmester T. Chapter 8 - Neuroglobin and Cytoglobin. In: Ghosh A, editor. The Smallest Biomolecules: Diatomics and their Interactions with Heme Proteins. Amsterdam: Elsevier; 2008. p. 203-18. https://doi.org/10.1016/B978-044452839-1.50009-7
McDonnell AM, Dang CH. Basic review of the cytochrome p450 system. J Adv Pract Oncol. 2013;4(4):263-8. https://doi.org/10.6004/jadpro.2013.4.4.7
Tuppy H, Kreil G. Cytochrome c. In: Lennarz WJ, Lane MD, editors. Encyclopedia of Biological Chemistry (Second Edition). Waltham: Academic Press; 2013. p. 599-601. https://doi.org/10.1016/B978-0-12-378630-2.00374-1
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-Activated Protein Kinase Induces a p53-Dependent Metabolic Checkpoint. Molecular cell. 2005;18(3):283-93. https://doi.org/10.1016/j.molcel.2005.03.027
Martínez-Diez M, Santamaría G, Ortega ÁD, Cuezva JM. Biogenesis and Dynamics of Mitochondria during the Cell Cycle: Significance of 3′UTRs. PLOS ONE. 2006;1(1):e107. https://doi.org/10.1371/journal.pone.0000107
Robey RB, Hay N. Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis. Seminars in cancer biology. 2009;19(1):25-31. https://doi.org/10.1016/j.semcancer.2008.11.010
Ghosh P, Vidal C, Dey S, Zhang L. Mitochondria Targeting as an Effective Strategy for Cancer Therapy. Int J Mol Sci. 2020;21(9). https://doi.org/10.3390/ijms21093363
Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun. 2017;482(3):426-31. https://doi.org/10.1016/j.bbrc.2016.11.088
Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nature Chemical Biology. 2015;11(1):9-15. https://doi.org/10.1038/nchembio.1712
Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 2015;21(6):805-21. https://doi.org/10.1016/j.cmet.2015.05.014
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nature Communications. 2020;11(1):102. https://doi.org/10.1038/s41467-019-13668-3
Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002;277(34):30409-12. https://doi.org/10.1074/jbc.R200006200
Kalainayakan SP, FitzGerald KE, Konduri PC, Vidal C, Zhang L. Essential roles of mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis. Cell Biosci. 2018;8:56. https://doi.org/10.1186/s13578-018-0257-8
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer. 2003;3(3):193-202. https://doi.org/10.1038/nrc1013
Todisco S, Convertini P, Iacobazzi V, Infantino V. TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma. Cancers. 2019;12(1). https://doi.org/10.3390/cancers12010068
Porporato PE, Filigheddu N, Pedro JMB-S, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Research. 2018;28(3):265-80. https://doi.org/10.1038/cr.2017.155
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proceedings of the National Academy of Sciences. 2007;104(49):19345-50. https://doi.org/10.1073/pnas.0709747104
Márquez J, Alonso FJ, Matés JM, Segura JA, Martín-Rufián M, Campos-Sandoval JA. Glutamine Addiction In Gliomas. Neurochemical research. 2017;42(6):1735-46. https://doi.org/10.1007/s11064-017-2212-1
Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer research. 2008;68(20):8547-54. https://doi.org/10.1158/0008-5472.CAN-08-1235
Wang D, Yin L, Wei J, Yang Z, Jiang G. ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumour Biol. 2017;39(4):1010428317698338. https://doi.org/10.1177/1010428317698338
Svensson RU, Shaw RJ. Lipid Synthesis Is a Metabolic Liability of Non-Small Cell Lung Cancer. Cold Spring Harbor symposia on quantitative biology. 2016;81:93-103. https://doi.org/10.1101/sqb.2016.81.030874
Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Frontiers in Pharmacology. 2014;5. https://doi.org/10.3389/fphar.2014.00061
Fukuda Y, Wang Y, Lian S, Lynch J, Nagai S, Fanshawe B, et al. Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis. JCI insight. 2017;2(15). https://doi.org/10.1172/jci.insight.92409
Wang J, Zhang J, Shi Y, Xu C, Zhang C, Wong YK, et al. Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity. ACS central science. 2017;3(7):743-50. https://doi.org/10.1021/acscentsci.7b00156
Sohoni S, Ghosh P, Wang T, Kalainayakan SP, Vidal C, Dey S, et al. Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non-Small Cell Lung Cancer Cells. Cancer research. 2019;79(10):2511-25. https://doi.org/10.1158/0008-5472.CAN-18-2156
Ye W, Zhang L. Heme deficiency causes apoptosis but does not increase ROS generation in HeLa cells. Biochem Biophys Res Commun. 2004;319(4):1065-71. https://doi.org/10.1016/j.bbrc.2004.05.089
Fiorito V, Chiabrando D, Petrillo S, Bertino F, Tolosano E. The Multifaceted Role of Heme in Cancer. Frontiers in oncology. 2020;9:1540. https://doi.org/10.3389/fonc.2019.01540
Sugiyama Y, Hagiya Y, Nakajima M, Ishizuka M, Tanaka T, Ogura S-I. The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis. Oncol Rep. 2014;31(3):1282-6. https://doi.org/10.3892/or.2013.2945
Fiorito V, Allocco AL, Petrillo S, Gazzano E, Torretta S, Marchi S, et al. The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation. Cell reports. 2021;35(11):109252. https://doi.org/10.1016/j.celrep.2021.109252
Allocco AL, Bertino F, Petrillo S, Chiabrando D, Riganti C, Bardelli A, et al. Inhibition of Heme Export and/or Heme Synthesis Potentiates Metformin Anti-Proliferative Effect on Cancer Cell Lines. Cancers. 2022;14(5). https://doi.org/10.3390/cancers14051230
Yu CP, Song YL, Zhu ZM, Huang B, Xiao YQ, Luo DY. Targeting TDO in cancer immunotherapy. Medical oncology (Northwood, London, England). 2017;34(5):73. https://doi.org/10.1007/s12032-017-0933-2
Hornyák L, Dobos N, Koncz G, Karányi Z, Páll D, Szabó Z, et al. The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Frontiers in Immunology. 2018;9. https://doi.org/10.3389/fimmu.2018.00151
Korolnek T, Hamza I. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol. 2014;5:126. https://doi.org/10.3389/fphar.2014.00126
Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell. 2017;170(6):1062-78. https://doi.org/10.1016/j.cell.2017.08.028
Shen J, Sheng X, Chang Z, Wu Q, Wang S, Xuan Z, et al. Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell reports. 2014;7(1):180-93. https://doi.org/10.1016/j.celrep.2014.02.042
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13(5):342-55. https://doi.org/10.1038/nrc3495
Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 2011;477(7363):225-8. https://doi.org/10.1038/nature10363
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