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Volume 30, Issue 1 (1-2026)
IBJ 2026, 30(1): 90-96 |
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Eskandari T, Shams M, Khanari A, Kahrizi A, Asgarian-Omran H, Valadan R, et al . Effect of HIF-1α and LDHA Blockade on Gene Expression of Tumor Immune Evasion in Myeloid Leukemia Cell Lines. IBJ 2026; 30 (1) :90-96
URL: http://ibj.pasteur.ac.ir/article-1-5324-en.html
URL: http://ibj.pasteur.ac.ir/article-1-5324-en.html
Tamana Eskandari 
, Mehrshad Shams , Ali Khanari , Amir Kahrizi , Hossein Asgarian-Omran , Reza Valadan , Mohsen Tehrani , Saeid Taghiloo *
, Mehrshad Shams , Ali Khanari , Amir Kahrizi , Hossein Asgarian-Omran , Reza Valadan , Mohsen Tehrani , Saeid Taghiloo *
Abstract:
Background: Tumor cells utilize metabolic reprogramming to obtain the energy required for rapid proliferation. In this study, we blocked two key factors, hypoxia-inducible factor 1-alpha (HIF-1α) and lactate dehydrogenase (LDHA), in the metabolic pathway in acute myeloid leukemia (AML) cell lines to evaluate their effect on the expression of genes involved in tumor evasion.
Methods: Silibinin and sodium oxamate, as HIF-1α and LDHA blockers, respectively, were used to treat K-562 and HL-60 cells. The MTT assay was used to assess cell viability, and quantitative reverse transcription PCR was used to measure the mRNA expression levels of PD-L1, CD47, and CD155.
Results: Both K-562 and HL-60 cells showed a significant decrease in CD47 expression. Additionally, HL-60 cells indicated a significant suppression of CD155 expression. In contrast, PD-L1 expression remained unchanged after treatment.
Conclusion: Our findings suggest that blocking signaling pathways involved in metabolic reprogramming of cancer cells could be a promising approach for modulating the expression of certain immune checkpoint ligands, warranting further investigation.
Methods: Silibinin and sodium oxamate, as HIF-1α and LDHA blockers, respectively, were used to treat K-562 and HL-60 cells. The MTT assay was used to assess cell viability, and quantitative reverse transcription PCR was used to measure the mRNA expression levels of PD-L1, CD47, and CD155.
Results: Both K-562 and HL-60 cells showed a significant decrease in CD47 expression. Additionally, HL-60 cells indicated a significant suppression of CD155 expression. In contrast, PD-L1 expression remained unchanged after treatment.
Conclusion: Our findings suggest that blocking signaling pathways involved in metabolic reprogramming of cancer cells could be a promising approach for modulating the expression of certain immune checkpoint ligands, warranting further investigation.
Type of Study: Full Length/Original Article |
Subject:
Cancer Biology
References
1. Pelcovits A, Niroula R. Acute Myeloid Leukemia: A review. R I Med J (2013). 2020;103(3):38-40.
2. Rashidi A, Fisher SI. Spontaneous remission of acute myeloid leukemia. Leuk Lymphoma. 2015;56(6):1727-34. [DOI:10.3109/10428194.2014.970545]
3. Yao H, Yang F, Li Y. Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review. Front Chem. 2022;10:1013670. [DOI:10.3389/fchem.2022.1013670]
4. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368(6487). [DOI:10.1126/science.aaw5473]
5. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20(1):51-6. [DOI:10.1016/j.gde.2009.10.009]
6. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286-99. [DOI:10.1016/j.cell.2009.05.045]
7. Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J Clin Invest. 2019;129(2):631-46. [DOI:10.1172/JCI123027]
8. Li H, Chai X. PDPK1 governs macrophage M2 polarization via hypoxia-driven CD47/AKT-glycolytic axis in endometriosis. Cell Signal. 2025;134:111922. [DOI:10.1016/j.cellsig.2025.111922]
9. Wang C, Sun C, Li M, Xia B, Wang Y, Zhang L, et al. Novel fully human anti-CD47 antibodies stimulate phagocytosis and promote elimination of AML cells. J Cell Physiol. 2021;236(6):4470-81. [DOI:10.1002/jcp.30163]
10. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114(8):1545-52. [DOI:10.1182/blood-2009-03-206672]
11. Sanchez-Correa B, Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Bergua JM, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE axis: Novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers. 2019;11(6):877. [DOI:10.3390/cancers11060877]
12. Gertner-Dardenne J, Fauriat C, Orlanducci F, Thibult ML, Pastor S, Fitzgibbon J, et al. The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: A potential way of immune escape for lymphoma cells. Blood. 2013;122(6):922-31. [DOI:10.1182/blood-2012-11-464685]
13. Noman MZ, Hasmim M, Lequeux A, Xiao M, Duhem C, Chouaib S, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: New opportunities and challenges. Cells. 2019;8(9):1083. [DOI:10.3390/cells8091083]
14. Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191(3):1486-95. [DOI:10.4049/jimmunol.1202702]
15. Jie XL, Wei JC, Wang D, Zhang XW, Lv MY, Lin YF, et al. CDC34 suppresses macrophage phagocytic activity and predicts poor response to immune checkpoint inhibitor in cancers. Cancer Lett. 2025;628:217822. [DOI:10.1016/j.canlet.2025.217822]
16. Xu C, Pei Y, Zhang X, Wang C, He M, Wan Z, et al. CD47/HIF-1α circuit promotes cell proliferation in hepatocellular carcinoma. Pathol Res Pract. 2025;276:156275. [DOI:10.1016/j.prp.2025.156275]
17. Wu H, Zhou X, Zhang Y, Zhou L, Wang Q, Wang T, et al. HIF-1α depletion regulates autophagy to improve arteriosclerosis obliterans of the lower extremities via the TSP-1/CD47 axis. Life Sci. 2025;378:123817. [DOI:10.1016/j.lfs.2025.123817]
18. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-90. [DOI:10.1084/jem.20131916]
19. Xanthopoulou ET, Kakouratos C, Nanos C, Gkegka AG, Kalaitzis C, Giatromanolaki A, et al. HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer. Med Oncol. 2023;40(5):151. [DOI:10.1007/s12032-023-02017-6]
20. Deep G, Agarwal R. Antimetastatic efficacy of silibinin: Molecular mechanisms and therapeutic potential against cancer. Cancer Metastasis Rev. 2010;29(3):447-63. [DOI:10.1007/s10555-010-9237-0]
21. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010;107(5):2037-42. [DOI:10.1073/pnas.0914433107]
22. Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4(3):e532. [DOI:10.1038/cddis.2013.60]
23. Deep G, Agarwal R. Targeting tumor microenvironment with silibinin: Promise and potential for a translational cancer chemopreventive strategy. Curr Cancer Drug Targets. 2013;13(5):486-99. [DOI:10.2174/15680096113139990041]
24. Kahrizi A, Asgarian-Omran H, Taghiloo S, Valadan R, Najafi A, Akbar A, et al. Targeting metabolic pathways in AML cell lines: Impact of hypoxia-inducible factor-1α (HIF-1α) and lactate dehydrogenase-A (LDH-A) inhibition. Iran Biomed J. 2025;29(6):427-36.
25. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. [DOI:10.1093/nar/29.9.e45]
26. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. [DOI:10.1038/nm730]
27. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54. [DOI:10.1056/NEJMoa1200690]
28. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271-85. [DOI:10.1016/j.cell.2009.05.046]
29. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012;109(17):6662-7. [DOI:10.1073/pnas.1121623109]
30. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923-37. [DOI:10.1016/j.ccell.2014.10.018]
31. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol.1927;8(6):519-30. [DOI:10.1085/jgp.8.6.519]
32. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447-54. [DOI:10.1128/mcb.12.12.5447-5454.1992]
33. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149-62. [DOI:10.1101/gad.12.2.149]
34. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271(51):32529-37. [DOI:10.1074/jbc.271.51.32529]
35. Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9(6):425-34. [DOI:10.1016/j.ccr.2006.04.023]
36. Deep G, Kumar R, Nambiar DK, Jain AK, Ramteke AM, Serkova NJ, et al. Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics. Mol Carcinog. 2017;56(3):833-48. [DOI:10.1002/mc.22537]
37. Dan W, Fan Y, Hou T, Wei Y, Liu B, Que T, et al. Silibinin inhibits the migration, invasion and epithelial-mesenchymal transition of prostate cancer by activating the autophagic degradation of YAP. J Cancer. 2022;13(13):3415-26. [DOI:10.7150/jca.63514]
38. Sellam LS, Zappasodi R, Chettibi F, Djennaoui D, Yahi-Ait Mesbah N, Amir-Tidadini ZC, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690:108479. [DOI:10.1016/j.abb.2020.108479]
39. Qiao T, Xiong Y, Feng Y, Guo W, Zhou Y, Zhao J, et al. Inhibition of LDH-A by oxamate enhances the efficacy of anti-PD-1 treatment in an NSCLC humanized mouse model. Front Oncol. 2021;11:632364. [DOI:10.3389/fonc.2021.632364]
40. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352(6282):227-31. [DOI:10.1126/science.aac9935]
41. Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von Hippel-Lindau gene mutation status. Eur Urol. 2016;70(4):623-32. [DOI:10.1016/j.eururo.2015.11.029]
42. Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T, et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol. 2014;25(10):1935-40. [DOI:10.1093/annonc/mdu242]
43. Lee S-K, Seo S-H, Kim B-S, Kim C-D, Lee J-H, Kang J-S, et al. IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J Dermatol Sci. 2005;40(2):95-103. [DOI:10.1016/j.jdermsci.2005.06.008]
44. Li W, Tanikawa T, Kryczek I, Xia H, Li G, Wu K, et al. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab. 2018;28(1):87-103. [DOI:10.1016/j.cmet.2018.04.022]
45. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell. 2018;172(5):1022-37. [DOI:10.1016/j.cell.2018.01.004]
46. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009;113(15):3503-11. [DOI:10.1182/blood-2008-08-173914]
47. Mateen S, Tyagi A, Agarwal C, Singh RP, Agarwal R. Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators. Mol Carcinog. 2010;49(3):247-58. [DOI:10.1002/mc.20595]
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