Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells

Document Type : Original Article


1 Department of Medical Biology, Ege University Medicine Faculty, 35100, Izmir, Turkey

2 Department of Molecular Biology and Genetics, Faculty of Science, Izmir Institute of Technology, 35433, Izmir, Turkey


Objective(s): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT3 to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells.
Materials and Methods: By using RNAi-mediated STAT3 gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT3 total, pTyr705, pSer727 protein expression levels, and metabolic activity as energy metabolism was determined in CML model K562 cells, in vitro.
Results: Targeting STAT3 sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT3 mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT3 silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT3-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response.
Conclusion: Targeting STAT3 is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism.


1. Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin Hematol 2010; 47:302–311. 
2. Jain P, Kantarjian H, Cortes J. Chronic myeloid leukemia: overview of new agents and comparative analysis. Curr Treat Options Oncol 2013; 14: 127–143. 
3. Gora-Tybor J. Emerging therapies in chronic  myeloid leukemia. Curr Cancer Drug Targets 2012; 12: 458–470. 
4. García-Gutiérrez V, Breccia M, Jabbour E, Mauro M, and Cortes JE. A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase. J Hematol Oncol 2022; 15:1–15. 
5. Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood 2009; 114:2168–2171. 
6. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880. 
7. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004; 117: 1281–1283. 
8. Valentino L, Pierre J. JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 2006; 71: 713–721. 
9. Ilaria RL, Van Etten RA. P210 and p190  BCR/ABL  induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996; 271: 31704–31710. 
10. Benekli M, Baumann H, Wetzler M. Targeting signal transducer and activator of transcription signaling pathway in leukemias. J Clin Oncol 2009; 27: 4422–4432. 
11. Demaria M, Camporeale A, Poli V. STAT3 and metabolism: how many ways to use a single molecule? Int J Cancer 2014; 135: 1997–2003. 
12. Kim BH, Yi EH, Ye SK. Signal transducer and activator of transcription 3 as a therapeutic target for cancer and the tumor microenvironment. Arch Pharm Res 2016; 39: 1085–1099. 
13. Hirano T, Nakajima K, Hibi M. Signaling mechanisms through gp130: A model of the cytokine system. Cytokine Growth Factor Rev 1997; 8: 241–252. 
14. Poli V, Camporeale A. STAT3-mediated metabolic reprograming in cellular transformation and implications for drug resistance. Front Oncol 2015; 5: 121-130. 
15. Demaria M, Poli V. Cell cycle from the nucleus to the mitochondria and back: The odyssey of a multitask STAT3. Cell Cycle2011; 10: 3221-3222.
16. Zaal EA, Berkers CR. The influence of metabolism on drug response in cancer. Front Oncol 2018; 8: 500-515. 
17. Baran Y, Ceylan C, Camgoz A. The roles of macromolecules in imatinib resistance of chronic myeloid leukemia cells by Fourier transform infrared spectroscopy. Biomed Pharmacother 2013; 67: 221–227. 
18. Sun CY, Nie J, Huang JP, Zheng GJ, Feng B. Targeting STAT3 inhibition to reverse cisplatin resistance. Biomed Pharmacother 2019; 117: 109135-109144. 
19. Tezcanlı Kaymaz B, Selvi N, Gokbulut AA, Aktan Ç, Gündüz C, Saydam G, et al. Suppression of STAT5A and STAT5B chronic myeloid leukemia cells via siRNA and antisense-oligonucleotide applications with the induction of apoptosis. Am J Blood Res 2013; 3: 58-70. 
20. Kaymaz BT, Selvi N, Gündüz C, Aktan Ç, Dalmizrak A, Saydam G, et al. Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K-562 with unmodified or chemically modified siRNAs and induction of apoptosis. Ann Hematol 2013; 92: 151–162. 
21. Shi Y, Zhang Z, Qu X, Zhu X, Zhao L, Wei R, et al. Roles of STAT3 in leukemia (review). Int J Oncol 2018; 53: 7–20. 
22. Ma L Di, Zhou M, Wen SH, Ni C, Jiang LJ, Fan J, et al. Effects of STAT3 silencing on fate of chronic myelogenous leukemia K562 cells. Leuk Lymphoma 2010; 51: 1326–1336. 
23. Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther 2008; 7: 3169–3175. 
24. Mencalha A, Victorino VJ, Cecchini R, Panis C. Mapping oxidative changes in breast cancer: understanding the basic to reach the clinics. Anticancer Res 2014; 34: 1127–1140. 
25. Yuzugullu H, Von T, Thorpe LM, Walker SR, Roberts TM, Frank DA, et al. NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov 2016; 2: 1–13. 
26. Cook AM, Li L, Ho Y, Lin A, Li L, Stein A, et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells. Blood 2014; 123: 2826–2837. 
27. Sasaki R, Ito S, Asahi M, Ishida Y. YM155 suppresses cell proliferation and induces cell death in human adult T-cell leukemia/lymphoma cells. Leuk Res 2015; 39: 1473–1479. 
28. Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu H-Y, Lin L-T, et al. Broad targeting of resistance to apoptosis in cancer HHS public access. Semin Cancer Biol 2015; 35: 78–103. 
29. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 2010;105:771-785.
30. Yucel B, Sonmez M. Repression of oxidative phosphorylation sensitizes leukemia cell lines to cytarabine. Hematology 2018; 23:330–336. 
31. Hoy SM. Patisiran: first global approval. Drugs 2018; 78: 1625–1631. 
32. Valle-Mendiola A and Soto-Cruz I. Energy metabolism in cancer: The roles of STAT3 and STAT5 in the regulation of metabolism-related genes. Cancers 2020; 12: 124-146. 
33. Noel BM, Ouellette SB, Navis C, Marholz L, Yang T-Y, Nguyen V, et al. Multi-omic profiling of TKI resistant K562 cells suggests metabolic reprogramming to promote cell survival. J Proteome Res 2019; 18: 1842-1856.
34. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M, et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006; 108:319–327. 
35. Kominsky DJ, Klawitter J, Brown JL, Boros LG, Melo J V, Eckhardt SG, et al. Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells. Clin Cancer Res 2009; 15: 3442–3450. 
36. Heiden MGV, Cantley LC, Thompson CB. Understanding the warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324:1029–1033. 
37. Chun KS, Jang JH, Kim DH. Perspectives regarding the intersections between STAT3 and oxidative metabolism in cancer. Cells 2020; 9: 2202-2219. 
38. Lee M, Hirpara JL, Eu J-Q, Sethi G, Wang L, Goh B-C, et al. Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors. Redox Biol 2018; 101073: 1-8. 
39. Lee H, Pal SK, Reckamp K, Figlin RA, Yu H. STAT3: a target to enhance antitumor immune response. Curr Top Microbiol Immunol 2010; 344: 41–59. 
40. Huynh J, Chand A, Gough D, Ernst M. Therapeutically exploiting STAT3 activity in cancer — using tissue repair as a road map. Nat Rev Cancer 2019; 19: 82–96. 
41. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 2018; 15: 234–248. 
42. Demaria M, Giorgi C, Lebiedzinska M, Esposito G, D’angeli L, Bartoli A, et al. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging (Albany NY) 2010; 2: 823–842. 
43. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports ras-dependent oncogenic transformation. Science 2009; 324: 1713–1716. 
44. Patel SB, Nemkov T, Stefanoni D, Benavides GA, Bassal MA, Crown BL, et al. Metabolic alterations mediated by STAT3 promotes drug persistence in CML. Leukemia 2021; 35: 3371–3382.
45. Zhang XY, Li M, Sun K, Chen XJ, Meng J, Wu L, et al. Decreased expression of GRIM-19 by DNA hypermethylation promotes aerobic glycolysis and cell proliferation in head and neck squamous cell carcinoma. Oncotarget 2015; 6: 101–115.