The Warburg effect in Multiple Myeloma and its microenvironment
Main Article Content
Abstract
This review highlights the current state of knowledge about the metabolism of cancer cells, especially with respect to “Warburg effect” in the pathogenesis of Multiple Myeloma (MM). Various pathways are known to contribute to the Warburg effect, characterized by an increased anaerobic glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS), resulting in elevated levels of lactic acid even in the presence of sufficient oxygen. For one thing it was shown, activation of PI3K/Akt/mTOR leads to enhanced expression of nutrient transporters and stimulation of glycolysis. In particular, glucose transporter (GLUT) 1, 4, 8 as well as 11 show elevated expression in MM and therefore enhanced glycolytic flux as well. Another important route manifesting the Warburg effect is peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its dual role within the production of reactive oxygen species (ROS). Furthermore, the stabilization and transcription of hypoxia-inducible factor 1 α (HIF1α) under tumor-attributed hypoxic conditions shows promising downstream mechanisms such as histone deacetylase (HDAC), which can be targeted and serve as adjuvant therapy to prolong overall survival of MM patients. In this paper we review the most promising and researched targets of the Warburg signaling are represented and analyzed upon their suitability as a therapeutic target in MM.
Article Details
How to Cite
KÜHNEL, Aline et al.
The Warburg effect in Multiple Myeloma and its microenvironment.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1466>. Date accessed: 19 apr. 2024.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2 Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013; 97(3):313–23.
3 Lemaire M, Deleu S, De Bruyne E, Van Valckenborgh E, Menu E, Vanderkerken K. The microenvironment and molecular biology of the multiple myeloma tumor. Adv Cancer Res. 2011; 110: 19-42.
4 Rajkumar SV. Evolving diagnostic criteria for multiple myeloma. ASH Education Book, December 5, 2015vol. 2015 no. 1 272-278.
5 Lentzsch S. et al. Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist. Therapeutic Advances in Hematology 2017; Vol. 8(2) 55–70.
6 Bianchi G. and N.C. Munshi, Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood, 2015. 125(20): p. 3049-3058.
7 Hideshima T., Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7(8):585–598.
8 Mahindra A., Hideshima T., Anderson K.C. Multiple myeloma: biology of the disease. Blood Rev., 24:5-11, 2010
9 Sripayapa P., Nagaia T., Hatanoa K., Kikuchib J., Furukawab Y., Ozawaa K. Romidepsin Overcomes Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma Cells. Acta Haematol 2014;132:1–4.
10 R. Berenstein, O. Blau, A. Nogai, M. Wächter, M. Schmidt-Hieber, A. Pezzutto, B. Dörken, I.W. Blau, Multiple Myeloma Cells Induce Mitochondrial Stress Response in Bone Marrow Mesenchymal Stromal Cells. Blood, 2014. 124(21): p.3357
11 Berenstein R., Blau O., Nogai A., Wächter M., Schmidt-Hieber M., Pezzutto A., Dörken B., Blau I.W., SIRT3 Modulates Mitochondrial Stress Response in Bone Marrow Mesenchymal Stromal Cells of Multiple Myeloma Patients. Blood 2015 126:5325
12 Berenstein R., In vitro Untersuchungen zur Charakterisierung molekularer Aberrationen in mesenchymalen Stromazellen beim Multiplen Myelom unter besonderer Berücksichtigung der Tumor-Stroma-Interaktion. Doktorarbeit 2016, Technische Universität Berlin
13 Walters et al., CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells. Cell Cycle. 2013 Oct 1; 12(19): 3175–3183.
14 German N.J. and M.C. Haigis, Sirtuins and the Metabolic Hurdles in Cancer. Curr Biol, 2015. 25(13): p. R569-83.
15 Senyilmaz D. and A.A. Teleman, Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep, 2015. 7: p. 41.
16 Minjong Lee and Jung-Hwan Yoon, Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015 August 26; 6(3): 148-161.
17 GJ Jones and CB Thompson, Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes and Development, 2009 Mar 1; 23(5): 537–548.
18 Wu H, Yang P, Hu W, et al. Overexpression of PKM2 promotes mitochondrial fusion through attenuated p53 stability. Oncotarget. 2016;7(47):78069-78082. doi:10.18632/oncotarget.12942.
19 Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, et al: Potent and selective inhibitors of PI3K delta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf. Bioorg Med Chem Lett 2012, 22(13):4296–4302
20 Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell. 2006;124:471–484.
21 Xi Y, Chen Y. J Cell Biochem. Oncogenic and Therapeutic Targeting of PTEN Loss in Bone Malignancies. 2015 Sep;116(9):1837-47. doi: 10.1002/jcb.25159.
22 Peterson, Timothy R. et al. “DEPTOR Is an mTOR Inhibitor Whose Frequent Overexpression in Multiple Myeloma Cells Promotes Their Survival.” Cell 137.5 (2009): 873–886. PMC. Web. 4 July 2017.
23 Qin, Xiaodan et al. “Extracellular Matrix Protein Reelin Promotes Myeloma Progression by Facilitating Tumor Cell Proliferation and Glycolysis.” Scientific Reports 7 (2017): 45305. PMC. Web. 5 July 2017.
24 Kwang Seok Ahn et al. Decursin chemosensitizes human multiple myeloma cells through inhibition of STAT3 signaling pathway. Cancer Lett. 2011 Feb 1;301(1):29-37. doi: 10.1016/j.canlet.2010.11.002. Epub 2010 Nov 30.
25 McBrayer, Samuel K. et al. “Multiple Myeloma Exhibits Novel Dependence on GLUT4, GLUT8, and GLUT11: Implications for Glucose Transporter-Directed Therapy.” Blood 119.20 (2012): 4686–4697. PMC. Web. 5 July 2017.
26 Phadngam S, Castiglioni A, Ferraresi A, Morani F, Follo C, Isidoro C. PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells. Oncotarget. 2016;7(51):84999-85020. doi:10.18632/oncotarget.13113.
27 Adekola KUA, Aydemir SD, Ma S, Zhou Z, Rosen ST, Shanmugam M. Investigating and Targeting Chronic Lymphocytic Leukemia Metabolism with the HIV Protease Inhibitor Ritonavir and Metformin. Leukemia & lymphoma. 2015;56(2):450-459. doi:10.3109/10428194.2014.922180.
28 Bajpai R, Matulis S, Wei C, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35(30):3955-3964. doi:10.1038/onc.2015.464.
29 Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005;106(3):1042-1047. doi:10.1182/blood-2005-01-0320.
30 Cao, D., Zhou, H., Zhao, J., Jin, L., Yu, W., Yan, H., Guo, T. (2014). PGC-1α integrates glucose metabolism and angiogenesis in multiple myeloma cells by regulating VEGF and GLUT-4. Oncology Reports, 31, 1205-1210. https://doi.org/10.3892/or.2014.2974
31 LeBleu V, O’Connell J, Gonzalez Herrera K, Wikman H, Pantel K, Haigis M, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol (2014) 16(10):992–1003,1–15.10.1038/ncb3039
32 Cao D, Jin L, Zhou H, Yu W, Hu Y, Guo T. Inhibition of PGC-1α after chemotherapy-mediated insult confines multiple myeloma cell survival by affecting ROS accumulation. Oncol Rep. 2015 Feb;33(2):899-904. doi: 10.3892/or.2014.3635. Epub 2014 Nov 28.
33 Lipchick BC, Fink EE, Nikiforov MA. Oxidative Stress and Proteasome Inhibitors in Multiple Myeloma. Pharmacological research. 2016;105:210-215. doi:10.1016/j.phrs.2016.01.029.
34 Ralph J.DeBerardinis, Julian J.Lum, Georgia Hatzivassiliou, Craig B.Thompson. The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Cell Press, Volume 7, Issue 1, January 2008, Pages 11-20.
35 Michele Cavoa et al. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment. Experimental Cell Research. Volume 328, Issue 2, 1 November 2014, Pages 444-455
36 Roberto Ria, Angelo Vacca et al. HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target. Clin Cancer Res February 15 2014 (20) (4) 847-858; DOI:10.1158/1078-0432. CCR-13-1950
37 Tirado-Vélez JM, Joumady I, Sáez-Benito A, Cózar-Castellano I, Perdomo G. Inhibition of Fatty Acid Metabolism Reduces Human Myeloma Cells Proliferation. Bhattacharya S, ed. PLoS ONE. 2012;7(9):e46484. doi:10.1371/journal.pone.0046484.46484.
38 Abramson HN. Kinase inhibitors as potential agents in the treatment of multiple myeloma. Oncotarget. 2016;7(49):81926-81968. doi:10.18632/oncotarget.10745.
39 Zadra G, Batista JL, Loda M. Dissecting the Dual Role of AMPK in Cancer: from Experimental to Human Studies. Molecular cancer research : MCR. 2015;13(7):1059-1072. doi:10.1158/1541-7786.MCR-15-0068.
40 Hanley N. Abramson. Kinase inhibitors as potential agents in the treatment of multiple myeloma. Oncotarget. 2016; 7:81926-81968. doi: 10.18632/oncotarget.10745
41 KR Carson, ML Bates, MH Tomasson. The skinny on obesity and plasma cell myeloma: a review of the literature Bone Marrow Transplantation (2014) 49, 1009–1015; doi:10.1038/bmt.2014.71; published online 12 May 2014.
42 Su-Hsin Chang, Suhong Luo, Theodore S. Thomas, Katiuscia K. O’Brian, Graham A. Colditz, Nils P. Carlsson, Kenneth R. Carson. Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study. J Natl Cancer Inst (2017) 109 (5): djw264.
43 Beverly A. Mock et al. Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation. Mol Cancer Ther May 18 2017 DOI: 10.1158/1535-7163.MCT-17-0171
44 Mathieu Laplante et al. Loss of hepatic DEPTOR alters the metabolic transition to fasting. Molecular Metabolism, Volume 6, Issue 5, May 2017, Pages 447–458.
45 Katarína Smolková et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. The International Journal of Biochemistry & Cell Biology, Volume 43, Issue 7, July 2011, Pages 950-968.
2 Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013; 97(3):313–23.
3 Lemaire M, Deleu S, De Bruyne E, Van Valckenborgh E, Menu E, Vanderkerken K. The microenvironment and molecular biology of the multiple myeloma tumor. Adv Cancer Res. 2011; 110: 19-42.
4 Rajkumar SV. Evolving diagnostic criteria for multiple myeloma. ASH Education Book, December 5, 2015vol. 2015 no. 1 272-278.
5 Lentzsch S. et al. Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist. Therapeutic Advances in Hematology 2017; Vol. 8(2) 55–70.
6 Bianchi G. and N.C. Munshi, Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood, 2015. 125(20): p. 3049-3058.
7 Hideshima T., Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7(8):585–598.
8 Mahindra A., Hideshima T., Anderson K.C. Multiple myeloma: biology of the disease. Blood Rev., 24:5-11, 2010
9 Sripayapa P., Nagaia T., Hatanoa K., Kikuchib J., Furukawab Y., Ozawaa K. Romidepsin Overcomes Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma Cells. Acta Haematol 2014;132:1–4.
10 R. Berenstein, O. Blau, A. Nogai, M. Wächter, M. Schmidt-Hieber, A. Pezzutto, B. Dörken, I.W. Blau, Multiple Myeloma Cells Induce Mitochondrial Stress Response in Bone Marrow Mesenchymal Stromal Cells. Blood, 2014. 124(21): p.3357
11 Berenstein R., Blau O., Nogai A., Wächter M., Schmidt-Hieber M., Pezzutto A., Dörken B., Blau I.W., SIRT3 Modulates Mitochondrial Stress Response in Bone Marrow Mesenchymal Stromal Cells of Multiple Myeloma Patients. Blood 2015 126:5325
12 Berenstein R., In vitro Untersuchungen zur Charakterisierung molekularer Aberrationen in mesenchymalen Stromazellen beim Multiplen Myelom unter besonderer Berücksichtigung der Tumor-Stroma-Interaktion. Doktorarbeit 2016, Technische Universität Berlin
13 Walters et al., CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells. Cell Cycle. 2013 Oct 1; 12(19): 3175–3183.
14 German N.J. and M.C. Haigis, Sirtuins and the Metabolic Hurdles in Cancer. Curr Biol, 2015. 25(13): p. R569-83.
15 Senyilmaz D. and A.A. Teleman, Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep, 2015. 7: p. 41.
16 Minjong Lee and Jung-Hwan Yoon, Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015 August 26; 6(3): 148-161.
17 GJ Jones and CB Thompson, Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes and Development, 2009 Mar 1; 23(5): 537–548.
18 Wu H, Yang P, Hu W, et al. Overexpression of PKM2 promotes mitochondrial fusion through attenuated p53 stability. Oncotarget. 2016;7(47):78069-78082. doi:10.18632/oncotarget.12942.
19 Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, et al: Potent and selective inhibitors of PI3K delta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf. Bioorg Med Chem Lett 2012, 22(13):4296–4302
20 Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell. 2006;124:471–484.
21 Xi Y, Chen Y. J Cell Biochem. Oncogenic and Therapeutic Targeting of PTEN Loss in Bone Malignancies. 2015 Sep;116(9):1837-47. doi: 10.1002/jcb.25159.
22 Peterson, Timothy R. et al. “DEPTOR Is an mTOR Inhibitor Whose Frequent Overexpression in Multiple Myeloma Cells Promotes Their Survival.” Cell 137.5 (2009): 873–886. PMC. Web. 4 July 2017.
23 Qin, Xiaodan et al. “Extracellular Matrix Protein Reelin Promotes Myeloma Progression by Facilitating Tumor Cell Proliferation and Glycolysis.” Scientific Reports 7 (2017): 45305. PMC. Web. 5 July 2017.
24 Kwang Seok Ahn et al. Decursin chemosensitizes human multiple myeloma cells through inhibition of STAT3 signaling pathway. Cancer Lett. 2011 Feb 1;301(1):29-37. doi: 10.1016/j.canlet.2010.11.002. Epub 2010 Nov 30.
25 McBrayer, Samuel K. et al. “Multiple Myeloma Exhibits Novel Dependence on GLUT4, GLUT8, and GLUT11: Implications for Glucose Transporter-Directed Therapy.” Blood 119.20 (2012): 4686–4697. PMC. Web. 5 July 2017.
26 Phadngam S, Castiglioni A, Ferraresi A, Morani F, Follo C, Isidoro C. PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells. Oncotarget. 2016;7(51):84999-85020. doi:10.18632/oncotarget.13113.
27 Adekola KUA, Aydemir SD, Ma S, Zhou Z, Rosen ST, Shanmugam M. Investigating and Targeting Chronic Lymphocytic Leukemia Metabolism with the HIV Protease Inhibitor Ritonavir and Metformin. Leukemia & lymphoma. 2015;56(2):450-459. doi:10.3109/10428194.2014.922180.
28 Bajpai R, Matulis S, Wei C, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35(30):3955-3964. doi:10.1038/onc.2015.464.
29 Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005;106(3):1042-1047. doi:10.1182/blood-2005-01-0320.
30 Cao, D., Zhou, H., Zhao, J., Jin, L., Yu, W., Yan, H., Guo, T. (2014). PGC-1α integrates glucose metabolism and angiogenesis in multiple myeloma cells by regulating VEGF and GLUT-4. Oncology Reports, 31, 1205-1210. https://doi.org/10.3892/or.2014.2974
31 LeBleu V, O’Connell J, Gonzalez Herrera K, Wikman H, Pantel K, Haigis M, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol (2014) 16(10):992–1003,1–15.10.1038/ncb3039
32 Cao D, Jin L, Zhou H, Yu W, Hu Y, Guo T. Inhibition of PGC-1α after chemotherapy-mediated insult confines multiple myeloma cell survival by affecting ROS accumulation. Oncol Rep. 2015 Feb;33(2):899-904. doi: 10.3892/or.2014.3635. Epub 2014 Nov 28.
33 Lipchick BC, Fink EE, Nikiforov MA. Oxidative Stress and Proteasome Inhibitors in Multiple Myeloma. Pharmacological research. 2016;105:210-215. doi:10.1016/j.phrs.2016.01.029.
34 Ralph J.DeBerardinis, Julian J.Lum, Georgia Hatzivassiliou, Craig B.Thompson. The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Cell Press, Volume 7, Issue 1, January 2008, Pages 11-20.
35 Michele Cavoa et al. HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment. Experimental Cell Research. Volume 328, Issue 2, 1 November 2014, Pages 444-455
36 Roberto Ria, Angelo Vacca et al. HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target. Clin Cancer Res February 15 2014 (20) (4) 847-858; DOI:10.1158/1078-0432. CCR-13-1950
37 Tirado-Vélez JM, Joumady I, Sáez-Benito A, Cózar-Castellano I, Perdomo G. Inhibition of Fatty Acid Metabolism Reduces Human Myeloma Cells Proliferation. Bhattacharya S, ed. PLoS ONE. 2012;7(9):e46484. doi:10.1371/journal.pone.0046484.46484.
38 Abramson HN. Kinase inhibitors as potential agents in the treatment of multiple myeloma. Oncotarget. 2016;7(49):81926-81968. doi:10.18632/oncotarget.10745.
39 Zadra G, Batista JL, Loda M. Dissecting the Dual Role of AMPK in Cancer: from Experimental to Human Studies. Molecular cancer research : MCR. 2015;13(7):1059-1072. doi:10.1158/1541-7786.MCR-15-0068.
40 Hanley N. Abramson. Kinase inhibitors as potential agents in the treatment of multiple myeloma. Oncotarget. 2016; 7:81926-81968. doi: 10.18632/oncotarget.10745
41 KR Carson, ML Bates, MH Tomasson. The skinny on obesity and plasma cell myeloma: a review of the literature Bone Marrow Transplantation (2014) 49, 1009–1015; doi:10.1038/bmt.2014.71; published online 12 May 2014.
42 Su-Hsin Chang, Suhong Luo, Theodore S. Thomas, Katiuscia K. O’Brian, Graham A. Colditz, Nils P. Carlsson, Kenneth R. Carson. Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study. J Natl Cancer Inst (2017) 109 (5): djw264.
43 Beverly A. Mock et al. Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation. Mol Cancer Ther May 18 2017 DOI: 10.1158/1535-7163.MCT-17-0171
44 Mathieu Laplante et al. Loss of hepatic DEPTOR alters the metabolic transition to fasting. Molecular Metabolism, Volume 6, Issue 5, May 2017, Pages 447–458.
45 Katarína Smolková et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. The International Journal of Biochemistry & Cell Biology, Volume 43, Issue 7, July 2011, Pages 950-968.