3-Bromopyruvate Inhibits the Growth and Glucose Metabolism of TNBC Xenografts in Nude Mice by Targeting c-Myc


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Background: Due to the lack of effective drug treatment, triple-negative breast cancer (TNBC) is prone to recurrence and metastasis after an operation. As a glycolytic inhibitor, 3-bromopyruvic acid (3-BrPA) can inhibit the proliferation and induce apoptosis of TNBC cells. However, whether it has similar effects in animal models remains unclear.

Objective: To observe the effect of 3-BrPA on the growth and glucose metabolism of human TNBC transplanted tumors in nude mice and to investigate the mechanism.

Methods: We constructed subcutaneous xenografts of human TNBC in nude mice and treated them with low, medium and high concentrations of 3-BrPA. After 15 days, nude mice were sacrificed to detect hexokinase (HK) activity and adenosine triphosphate (ATP) content in tumor tissues. Hematoxylin-eosin (HE) staining was used to detect the damage of transplanted tumors and liver and kidney in nude mice, which 3-BrPA caused. The expression of c-Myc in tumor tissues was detected by Immunohistochemistry (IHC). Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the apoptosis of tumor tissues. Besides, the expressions of Cytc, Bax, Bcl-2 and Caspase-9 were detected by Western blotting.

Results: Compared with the control group, intraperitoneal injection of 3-BrPA inhibited the growth of human TNBC transplant tumors, decreased HK activity and ATP production in tumor tissues, disrupted the tissue structure of transplant tumors, and did not significantly damage liver and kidney tissues. IHC staining and Western blotting showed that 3-BrPA could decrease the expression of c-Myc and Bcl-2, increase the expression of Cyt -c, Bax and Caspase-9 expression and promote apoptosis in tumor tissues.

Conclusion: The above data indicate that 3-BrPA inhibits the growth of human TNBC transplanted tumors and promotes their apoptosis. Its anti-cancer mechanism might reduce HK activity by down-regulating c-Myc expression, eventually leading to decreased glycolytic pathway energy production and promoting apoptosis of transplanted tumors.

Sobre autores

Jian-Min Pan

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Jia-Chen Li

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Cheng Yang

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Wang-Fa Xiao

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Qi-Shang Li

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Xiao-Hui Luo

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Xiao-Dong Zhang

Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Zimmer, A.S. Triple-negative breast cancer central nervous system metastases from the laboratory to the clinic. Cancer J., 2021, 27(1), 76-82. doi: 10.1097/PPO.0000000000000503 PMID: 33475296
  3. Vagia, E.; Mahalingam, D.; Cristofanilli, M. The landscape of targeted therapies in TNBC. Cancers, 2020, 12(4), 916. doi: 10.3390/cancers12040916 PMID: 32276534
  4. Chen, F.; Wang, Q.; Yu, X.; Yang, N.; Wang, Y.; Zeng, Y.; Zheng, Z.; Zhou, F.; Zhou, Y. MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis. Cell Death Dis., 2021, 12(4), 370. doi: 10.1038/s41419-021-03661-4 PMID: 33824311
  5. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol., 1927, 8(6), 519-530. doi: 10.1085/jgp.8.6.519 PMID: 19872213
  6. Fan, T.; Sun, G.; Sun, X.; Zhao, L.; Zhong, R.; Peng, Y. Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: Implications in tumor treatment. Cancers, 2019, 11(3), 317. doi: 10.3390/cancers11030317 PMID: 30845728
  7. Kim, S.; Kim, D.H.; Jung, W.H.; Koo, J.S. Metabolic phenotypes in triple-negative breast cancer. Tumour Biol., 2013, 34(3), 1699-1712. doi: 10.1007/s13277-013-0707-1 PMID: 23443971
  8. Fatma, H.; Siddique, H.R. Role of long non-coding RNAs and MYC interaction in cancer metastasis: A possible target for therapeutic intervention. Toxicol. Appl. Pharmacol., 2020, 399, 115056. doi: 10.1016/j.taap.2020.115056 PMID: 32445756
  9. Constantinou, C.; Papadopoulos, S.; Karyda, E.; Alexopoulos, A.; Agnanti, N.; Batistatou, A.; Harisis, H. Expression and clinical significance of Claudin-7, PDL-1, PTEN, c-Kit, c-Met, c-Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in triple-negative breast cancer-A single centre prospective observational study. In Vivo, 2018, 32(2), 303-311. PMID: 29475913
  10. Shen, S.; Yao, T.; Xu, Y.; Zhang, D.; Fan, S.; Ma, J. CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc. Mol. Cancer, 2020, 19(1), 151. doi: 10.1186/s12943-020-01269-4 PMID: 33106166
  11. Ko, Y.H.; Pedersen, P.L.; Geschwind, J.F. Glucose catabolism in the rabbit VX2 tumor model for liver cancer: Characterization and targeting hexokinase. Cancer Lett., 2001, 173(1), 83-91. doi: 10.1016/S0304-3835(01)00667-X PMID: 11578813
  12. Zhang, B.; Chan, S.H.; Liu, X.Q.; Shi, Y.Y.; Dong, Z.X.; Shao, X.R.; Zheng, L.Y.; Mai, Z.Y.; Fang, T.L.; Deng, L.Z.; Zhou, D.S.; Chen, S.N.; Li, M.; Zhang, X.D. Targeting hexokinase 2 increases the sensitivity of oxaliplatin by Twist1 in colorectal cancer. J. Cell. Mol. Med., 2021, 25(18), 8836-8849. doi: 10.1111/jcmm.16842 PMID: 34378321
  13. Jardim-Messeder, D.; Moreira-Pacheco, F. 3-Bromopyruvic acid inhibits tricarboxylic acid cycle and glutaminolysis in HepG2 cells. Anticancer Res., 2016, 36(5), 2233-2241. PMID: 27127128
  14. Sun, X.; Sun, G.; Huang, Y.; Hao, Y.; Tang, X.; Zhang, N.; Zhao, L.; Zhong, R.; Peng, Y. 3-Bromopyruvate regulates the status of glycolysis and BCNU sensitivity in human hepatocellular carcinoma cells. Biochem. Pharmacol., 2020, 177, 113988. doi: 10.1016/j.bcp.2020.113988 PMID: 32330495
  15. Guo, X.; Zhang, X.; Wang, T.; Xian, S.; Lu, Y. 3-Bromopyruvate and sodium citrate induce apoptosis in human gastric cancer cell line MGC-803 by inhibiting glycolysis and promoting mitochondria-regulated apoptosis pathway. Biochem. Biophys. Res. Commun., 2016, 475(1), 37-43. doi: 10.1016/j.bbrc.2016.04.151 PMID: 27163639
  16. Zhao, B.; Aggarwal, A.; Marshall, J.A.; Barletta, J.A.; Kijewski, M.F.; Lorch, J.H.; Nehs, M.A. Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer. Surgery, 2022, 171(1), 227-234. doi: 10.1016/j.surg.2021.05.055 PMID: 34334212
  17. Wang, T.A.; Xian, S.L.; Guo, X.Y.; Zhang, X.D.; Lu, Y.F. Combined 18F-FDG PET/CT imaging and a gastric orthotopic xenograft model in nude mice are used to evaluate the efficacy of glycolysis-targeted therapy. Oncol. Rep., 2018, 39(1), 271-279. PMID: 29115645
  18. Bai, X.; Ni, J.; Beretov, J.; Graham, P.; Li, Y. Triple-negative breast cancer therapeutic resistance: Where is the Achilles' heel? Cancer Lett., 2021, 497, 100-111. doi: 10.1016/j.canlet.2020.10.016 PMID: 33069769
  19. Jhan, J.R.; Andrechek, E.R. Triple-negative breast cancer and the potential for targeted therapy. Pharmacogenomics, 2017, 18(17), 1595-1609. doi: 10.2217/pgs-2017-0117 PMID: 29095114
  20. Li, J.; Pan, J.; Liu, Y.; Luo, X.; Yang, C.; Xiao, W.; Li, Q.; Yang, L.; Zhang, X. 3 Bromopyruvic acid regulates glucose metabolism by targeting the c Myc/TXNIP axis and induces mitochondria mediated apoptosis in TNBC cells. Exp. Ther. Med., 2022, 24(2), 520. doi: 10.3892/etm.2022.11447 PMID: 35837063
  21. Cocco, S.; Piezzo, M.; Calabrese, A.; Cianniello, D.; Caputo, R.; Di Lauro, V.; Fusco, G.; di Gioia, G.; Licenziato, M.; de Laurentiis, M. Biomarkers in triple-negative breast cancer: State-of-the-art and future perspectives. Int. J. Mol. Sci., 2020, 21(13), 4579. doi: 10.3390/ijms21134579 PMID: 32605126
  22. Shin, E.; Koo, J.S. Glucose metabolism and glucose transporters in breast cancer. Front. Cell Dev. Biol., 2021, 9, 728759. doi: 10.3389/fcell.2021.728759 PMID: 34552932
  23. Li, L.K.; Zhang, X.J.; Wang, L.M.; Hu, J.Y.; Cao, F.H. Inhibitory effect of 3-bromopyruvate on the proliferation, migration and invasive ability of prostate cancer PC-3 cells. Zhonghua Nan Ke Xue, 2020, 26(1), 17-23. PMID: 33345472
  24. Garcia, S.N.; Guedes, R.C.; Marques, M.M. Unlocking the potential of HK2 in cancer metabolism and therapeutics. Curr. Med. Chem., 2020, 26(41), 7285-7322. doi: 10.2174/0929867326666181213092652 PMID: 30543165
  25. Klepinin, A.; Ounpuu, L.; Mado, K.; Truu, L.; Chekulayev, V.; Puurand, M.; Shevchuk, I.; Tepp, K.; Planken, A.; Kaambre, T. The complexity of mitochondrial outer membrane permeability and VDAC regulation by associated proteins. J. Bioenerg. Biomembr., 2018, 50(5), 339-354. doi: 10.1007/s10863-018-9765-9 PMID: 29998379
  26. Gan, L.; Xiu, R.; Ren, P.; Yue, M.; Su, H.; Guo, G.; Xiao, D.; Yu, J.; Jiang, H.; Liu, H.; Hu, G.; Qing, G. Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters. Oncogene, 2016, 35(23), 3037-3048. doi: 10.1038/onc.2015.360 PMID: 26434591
  27. Wu, N.; Zheng, B.; Shaywitz, A.; Dagon, Y.; Tower, C.; Bellinger, G.; Shen, C.H.; Wen, J.; Asara, J.; McGraw, T.E.; Kahn, B.B.; Cantley, L.C. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell, 2013, 49(6), 1167-1175. doi: 10.1016/j.molcel.2013.01.035 PMID: 23453806
  28. Shen, L.; O'Shea, J.M.; Kaadige, M.R.; Cunha, S.; Wilde, B.R.; Cohen, A.L.; Welm, A.L.; Ayer, D.E. Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc. Natl. Acad. Sci. USA, 2015, 112(17), 5425-5430. doi: 10.1073/pnas.1501555112 PMID: 25870263
  29. Skaripa-Koukelli, I.; Hauton, D.; Walsby-Tickle, J.; Thomas, E.; Owen, J.; Lakshminarayanan, A.; Able, S.; McCullagh, J.; Carlisle, R.C.; Vallis, K.A. 3-Bromopyruvate-mediated MCT1-dependent metabolic perturbation sensitizes triple negative breast cancer cells to ionizing radiation. Cancer Metab., 2021, 9(1), 37. doi: 10.1186/s40170-021-00273-6 PMID: 34649623
  30. Fang, Y.; Shen, Z.Y.; Zhan, Y.Z.; Feng, X.C.; Chen, K.L.; Li, Y.S.; Deng, H.J.; Pan, S.M.; Wu, D.H.; Ding, Y. CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis. Nat. Commun., 2019, 10(1), 3981. doi: 10.1038/s41467-019-11662-3 PMID: 31484922
  31. Dadsena, S.; King, L.E.; García-Sáez, A.J. Apoptosis regulation at the mitochondria membrane level. Biochim. Biophys. Acta Biomembr., 2021, 1863(12), 183716. doi: 10.1016/j.bbamem.2021.183716 PMID: 34343535
  32. Zraik, I.M.; Heß-Busch, Y. Management of chemotherapy side effects and their long-term sequelae. Urologe A, 2021, 60(7), 862-871. doi: 10.1007/s00120-021-01569-7 PMID: 34185118
  33. Abdollahi, R.; Najafi, S.; Razmpoosh, E.; Shoormasti, R.S.; Haghighat, S.; Raji Lahiji, M.; Chamari, M.; Asgari, M.; Cheshmazar, E.; Zarrati, M. The effect of dietary intervention along with nutritional education on reducing the gastrointestinal side effects caused by chemotherapy among women with breast cancer. Nutr. Cancer, 2019, 71(6), 922-930. doi: 10.1080/01635581.2019.1590608 PMID: 30945949
  34. Li, S.; Yuan, S.; Zhao, Q.; Wang, B.; Wang, X.; Li, K. Quercetin enhances chemotherapeutic effect of doxorubicin against human breast cancer cells while reducing toxic side effects of it. Biomed. Pharmacother., 2018, 100, 441-447. doi: 10.1016/j.biopha.2018.02.055 PMID: 29475141
  35. Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci., 2020, 21(9), 3233. doi: 10.3390/ijms21093233 PMID: 32370233
  36. Linke, C.; Wösle, M.; Harder, A. Anti-cancer agent 3-bromopyruvate reduces growth of MPNST and inhibits metabolic pathways in a representative in vitro model. BMC Cancer, 2020, 20(1), 896. doi: 10.1186/s12885-020-07397-w PMID: 32948135
  37. Nikravesh, H.; Khodayar, M.J.; Behmanesh, B.; Mahdavinia, M.; Teimoori, A.; Alboghobeish, S.; Zeidooni, L. The combined effect of dichloroacetate and 3-bromopyruvate on glucose metabolism in colorectal cancer cell line, HT-29; the mitochondrial pathway apoptosis. BMC Cancer, 2021, 21(1), 903. doi: 10.1186/s12885-021-08564-3 PMID: 34364387
  38. Chapiro, J.; Sur, S.; Savic, L.J.; Ganapathy-Kanniappan, S.; Reyes, J.; Duran, R.; Thiruganasambandam, S.C.; Moats, C.R.; Lin, M.; Luo, W.; Tran, P.T.; Herman, J.M.; Semenza, G.L.; Ewald, A.J.; Vogelstein, B.; Geschwind, J.F. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clin. Cancer Res., 2014, 20(24), 6406-6417. doi: 10.1158/1078-0432.CCR-14-1271 PMID: 25326230

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