Combined Application of Salinomycin and ATRA Induces Apoptosis and Differentiation of Acute Myeloid Leukemia Cells by Inhibiting WNT/β-Catenin Pathway

  • Authors: Xi H.1, Lu H.1, Weng X.2, Sheng Y.1, Wu J.3, Li L.4, Cai X.2
  • Affiliations:
    1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
    2. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
    3. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
    4. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
  • Issue: Vol 23, No 9 (2023)
  • Pages: 1074-1084
  • Section: Oncology
  • URL: https://kld-journal.fedlab.ru/1871-5206/article/view/694402
  • DOI: https://doi.org/10.2174/1871520623666230110121629
  • ID: 694402

Cite item

Full Text

Abstract

Background and objective:All-trans retinoic acid (ATRA) is only effective in acute promyelocytic leukemia (APL), but not in other subtype of acute myeloid leukemia (AML). Salinomycin targets tumor cells rather than non-tumorigenic cells, and WNT/β-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity. There is a crosstalk between RA and WNT/β-catenin pathway. Here, we investigate the effect of the combination of salinomycin and ATRA (S+RA) in non-APL AML cells.

Methods: Apoptosis was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11c expression and morphology. To explore the underlying mechanisms, Western blot analysis and mitochondrial transmembrane potentials (m) were used.

Results & Discussion:S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA inhibited the β-catenin signal pathway as determined by the decreased protein levels of β-catenin, the low-density lipoprotein receptor-related proteins 6 (LRP6), and its downstream proteins such as survivin, c-Myc, caspase-3/7, cdc25A and cyclinD1 and reduced phosphorylation level of GSK3β S9. S+RA also increased the protein levels of CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed m. The above molecular and cellular changes induced by S+RA were inhibited by β-catenin specific activator and promoted by β-catenin specific inhibitor.

Conclusion: S+RA induced differentiation by β-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and suppression of c-Myc. S+RA triggered apoptosis through β-catenin-inhibition-regulated m collapse and caspase-3/7 activation. Taken together, our findings may provide novel therapeutic strategies for AML patients by targeting the WNT/β-catenin pathway.

About the authors

Hui-Min Xi

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Hao Lu

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Xiang-Qin Weng

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,

Email: info@benthamscience.net

Yan Sheng

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Jing Wu

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai

Email: info@benthamscience.net

Lu Li

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Xun Cai

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai,, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,

Author for correspondence.
Email: info@benthamscience.net

References

  1. Kantarjian, H.; Kadia, T.; DiNardo, C.; Daver, N.; Borthakur, G.; Jabbour, E.; Garcia-Manero, G.; Konopleva, M.; Ravandi, F. Acute myeloid leukemia: Current progress and future directions. Blood Cancer J., 2021, 11(2), 41. doi: 10.1038/s41408-021-00425-3 PMID: 33619261
  2. Huang, M.E.; Ye, Y.C.; Chen, S.R.; Chai, J.R.; Lu, J.X.; Zhoa, L.; Gu, L.J.; Wang, Z.Y. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood, 1988, 72(2), 567-572. doi: 10.1182/blood.V72.2.567.567 PMID: 3165295
  3. Taciak, B.; Pruszynska, I.; Kiraga, L.; Bialasek, M.; Krol, M. Wnt signaling pathway in development and cancer. J. Physiol. Pharmacol., 2018, 69(2), 12. PMID: 29980141
  4. Reya, T.; Duncan, A.W.; Ailles, L.; Domen, J.; Scherer, D.C.; Willert, K.; Hintz, L.; Nusse, R.; Weissman, I.L. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 2003, 423(6938), 409-414. doi: 10.1038/nature01593 PMID: 12717450
  5. Staal, F.J.T.; Clevers, H.C. WNT signalling and haematopoiesis: A WNT-WNT situation. Nat. Rev. Immunol., 2005, 5(1), 21-30. doi: 10.1038/nri1529 PMID: 15630426
  6. Ysebaert, L.; Chicanne, G.; Demur, C.; De Toni, F.; Prade-Houdellier, N.; Ruidavets, J-B.; Mansat-De Mas, V.; Rigal-Huguet, F.; Laurent, G.; Payrastre, B.; Manenti, S.; Racaud-Sultan, C. Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia, 2006, 20(7), 1211-1216. doi: 10.1038/sj.leu.2404239 PMID: 16688229
  7. Mikesch, J-H.; Steffen, B.; Berdel, W.E.; Serve, H.; Müller-Tidow, C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia, 2007, 21(8), 1638-1647. doi: 10.1038/sj.leu.2404732 PMID: 17554387
  8. Wang, Y.; Krivtsov, A.V.; Sinha, A.U.; North, T.E.; Goessling, W.; Feng, Z.; Zon, L.I.; Armstrong, S.A. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science, 2010, 327(5973), 1650-1653. doi: 10.1126/science.1186624 PMID: 20339075
  9. Kode, A.; Manavalan, J.S.; Mosialou, I.; Bhagat, G.; Rathinam, C.V.; Luo, N.; Khiabanian, H.; Lee, A.; Murty, V.V.; Friedman, R.; Brum, A.; Park, D.; Galili, N.; Mukherjee, S.; Teruya-Feldstein, J.; Raza, A.; Rabadan, R.; Berman, E.; Kousteni, S. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature, 2014, 506(7487), 240-244. doi: 10.1038/nature12883 PMID: 24429522
  10. Cardona-Echeverry, A.; Prada-Arismendy, J. Deciphering the role of Wnt signaling in acute myeloid leukemia prognosis: How alterations in DNA methylation come into play in patients' prognosis. J. Cancer Res. Clin. Oncol., 2020, 146(12), 3097-3109. doi: 10.1007/s00432-020-03407-3 PMID: 32980885
  11. Jiang, X.; Mak, P.Y.; Mu, H.; Tao, W.; Mak, D.H.; Kornblau, S.; Zhang, Q.; Ruvolo, P.; Burks, J.K.; Zhang, W.; McQueen, T.; Pan, R.; Zhou, H.; Konopleva, M.; Cortes, J.; Liu, Q.; Andreeff, M.; Carter, B.Z. Disruption of Wnt/β-catenin exerts antileukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia. Clin. Cancer Res., 2018, 24(10), 2417-2429. doi: 10.1158/1078-0432.CCR-17-1556 PMID: 29463558
  12. Suknuntha, K.; Thita, T.; Togarrati, P.P.; Ratanachamnong, P.; Wongtrakoongate, P.; Srihirun, S.; Slukvin, I.; Hongeng, S. Wnt signaling inhibitor FH535 selectively inhibits cell proliferation and potentiates imatinib-induced apoptosis in myeloid leukemia cell lines. Int. J. Hematol., 2017, 105(2), 196-205. doi: 10.1007/s12185-016-2116-x PMID: 27766528
  13. Takam Kamga, P.; Dal Collo, G.; Cassaro, A.; Bazzoni, R.; Delfino, P.; Adamo, A.; Bonato, A.; Carbone, C.; Tanasi, I.; Bonifacio, M.; Krampera, M. Small molecule inhibitors of microenvironmental Wnt/β-catenin signaling enhance the chemosensitivity of acute myeloid leukemia. Cancers, 2020, 12(9), 2696. doi: 10.3390/cancers12092696 PMID: 32967262
  14. Easwaran, V.; Pishvaian, M.; Salimuddin; Byers, S. Cross-regulation of β-catenin-LEF/TCF and retinoid signaling pathways. Curr. Biol., 1999, 9(23), 1415-1419. doi: 10.1016/S0960-9822(00)80088-3 PMID: 10607566
  15. Zhu, X.; Wang, W.; Zhang, X.; Bai, J.; Chen, G.; Li, L.; Li, M. All-trans retinoic acid-induced deficiency of the Wnt/β-catenin pathway enhances hepatic carcinoma stem cell differentiation. PLoS One, 2015, 10(11), e0143255. doi: 10.1371/journal.pone.0143255 PMID: 26571119
  16. Wang, S.; Huang, H.; Xiang, H.; Gu, B.; Li, W.; Chen, L.; Zhang, M. Wnt signaling modulates routes of retinoic acid-induced differentiation of embryonic stem cells. Stem Cells Dev., 2019, 28(19), 1334-1345. doi: 10.1089/scd.2019.0065 PMID: 31337269
  17. Dewangan, J.; Srivastava, S.; Rath, S.K. Salinomycin: A new paradigm in cancer therapy. Tumour Biol., 2017, 39(3) doi: 10.1177/1010428317695035 PMID: 28349817
  18. Zhao, Y.; Zhong, L.; Liu, L.; Yao, S.F.; Chen, M.; Li, L.W.; Shan, Z.L.; Xiao, C.L.; Gan, L.G.; Xu, T.; Liu, B.Z. Salinomycin induces apoptosis and differentiation in human acute promyelocytic leukemia cells. Oncol. Rep., 2018, 40(2), 877-886. doi: 10.3892/or.2018.6513 PMID: 29989650
  19. Roulston, G.D.R.; Burt, C.L.; Kettyle, L.M.J.; Matchett, K.B.; Keenan, H.L.; Mulgrew, N.M.; Ramsey, J.M.; Dougan, C.; McKiernan, J.; Grishagin, I.V.; Mills, K.I.; Thompson, A. Low-dose salinomycin induces anti-leukemic responses in AML and MLL. Oncotarget, 2016, 7(45), 73448-73461. doi: 10.18632/oncotarget.11866 PMID: 27612428
  20. Fuchs, D.; Daniel, V.; Sadeghi, M.; Opelz, G.; Naujokat, C. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem. Biophys. Res. Commun., 2010, 394(4), 1098-1104. doi: 10.1016/j.bbrc.2010.03.138 PMID: 20350531
  21. Lu, D.; Choi, M.Y.; Yu, J.; Castro, J.E.; Kipps, T.J.; Carson, D.A. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc. Natl. Acad. Sci. USA, 2011, 108(32), 13253-13257. doi: 10.1073/pnas.1110431108 PMID: 21788521
  22. Li, Y.P.; Said, F.; Gallagher, R.E. Retinoic acid-resistant HL-60 cells exclusively contain mutant retinoic acid receptor-α. Blood, 1994, 83(11), 3298-3302. doi: 10.1182/blood.V83.11.3298.3298 PMID: 8193365
  23. Lu, H.; Li, Z.; Ding, M.; Liang, C.; Weng, X.; Sheng, Y.; Wu, J.; Cai, X. Trametinib enhances ATRA-induced differentiation in AML cells. Leuk. Lymphoma, 2021, 62(14), 3361-3372. doi: 10.1080/10428194.2021.1961231 PMID: 34355652
  24. Liang, C.; Ding, M.; Weng, X.Q.; Sheng, Y.; Wu, J.; Li, Z.Y.; Cai, X. Combination of enzastaurin and ATRA exerts dose-dependent dual effects on ATRA-resistant acute promyelocytic leukemia cells. Am. J. Cancer Res., 2019, 9(5), 906-926. PMID: 31218101
  25. Tetsu, O.; McCormick, F. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature, 1999, 398(6726), 422-426. doi: 10.1038/18884 PMID: 10201372
  26. Vijayakumar, S.; Liu, G.; Rus, I.A.; Yao, S.; Chen, Y.; Akiri, G.; Grumolato, L.; Aaronson, S.A. High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A. Cancer Cell, 2011, 19(5), 601-612. doi: 10.1016/j.ccr.2011.03.010 PMID: 21575861
  27. Ma, H.; Nguyen, C.; Lee, K.S.; Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene, 2005, 24(22), 3619-3631. doi: 10.1038/sj.onc.1208433 PMID: 15782138
  28. Huang, Y.H.; Yeh, C.T. Functional compartmentalization of HSP60-survivin interaction between mitochondria and cytosol in cancer cells. Cells, 2019, 9(1), 23. doi: 10.3390/cells9010023 PMID: 31861751
  29. van de Wetering, M.; Sancho, E.; Verweij, C.; de Lau, W.; Oving, I.; Hurlstone, A.; van der Horn, K.; Batlle, E.; Coudreuse, D.; Haramis, A.P.; Tjon-Pon-Fong, M.; Moerer, P.; van den Born, M.; Soete, G.; Pals, S.; Eilers, M.; Medema, R.; Clevers, H. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell, 2002, 111(2), 241-250. doi: 10.1016/S0092-8674(02)01014-0 PMID: 12408868
  30. Song, J.H.; Park, E.; Kim, M.S.; Cho, K.M.; Park, S.H.; Lee, A.; Song, J.; Kim, H.J.; Koh, J.T.; Kim, T.S. L -Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH)2 D3-induced myeloid differentiation in acute myeloid leukemia cells. Int. J. Cancer, 2017, 140(10), 2364-2374. doi: 10.1002/ijc.30662 PMID: 28224619
  31. Li, Z.Y.; Liang, C.; Ding, M.; Weng, X.Q.; Sheng, Y.; Wu, J.; Lu, H.; Cai, X. Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells. Am. J. Transl. Res., 2020, 12(12), 7836-7854. PMID: 33437364
  32. Sheng, Y.; Ju, W.; Huang, Y.; Li, J.; Ozer, H.; Qiao, X.; Qian, Z. Activation of wnt/β-catenin signaling blocks monocyte-macrophage differentiation through antagonizing PU.1-targeted gene transcription. Leukemia, 2016, 30(10), 2106-2109. doi: 10.1038/leu.2016.146 PMID: 27211263
  33. Moldes, M.; Zuo, Y.; Morrison, R.F.; Silva, D.; Park, B.H.; Liu, J.; Farmer, S.R. Peroxisome-proliferator-activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis. Biochem. J., 2003, 376(3), 607-613. doi: 10.1042/bj20030426 PMID: 12954078
  34. Rosenbauer, F.; Owens, B.M.; Yu, L.; Tumang, J.R.; Steidl, U.; Kutok, J.L.; Clayton, L.K.; Wagner, K.; Scheller, M.; Iwasaki, H.; Liu, C.; Hackanson, B.; Akashi, K.; Leutz, A.; Rothstein, T.L.; Plass, C.; Tenen, D.G. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nat. Genet., 2006, 38(1), 27-37. doi: 10.1038/ng1679 PMID: 16311598
  35. Hirouchi, T.; Takabatake, T.; Yoshida, K.; Nitta, Y.; Nakamura, M.; Tanaka, S.; Ichinohe, K.; Oghiso, Y.; Tanaka, K. Upregulation of c-myc gene accompanied by PU.1 deficiency in radiation-induced acute myeloid leukemia in mice. Exp. Hematol., 2008, 36(7), 871-885. doi: 10.1016/j.exphem.2008.01.015 PMID: 18375040
  36. Park, D.J.; Chumakov, A.M.; Vuong, P.T.; Chih, D.Y.; Gombart, A.F.; Miller, W.H., Jr; Koeffler, H.P. CCAAT/enhancer binding protein ε is a potential retinoid target gene in acute promyelocytic leukemia treatment. J. Clin. Invest., 1999, 103(10), 1399-1408. doi: 10.1172/JCI2887 PMID: 10330422
  37. Yoshida, H.; Ichikawa, H.; Tagata, Y.; Katsumoto, T.; Ohnishi, K.; Akao, Y.; Naoe, T.; Pandolfi, P.P.; Kitabayashi, I. PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU.1-induced C/EB Pepsilon expression in myeloid differentiation. Mol. Cell. Biol., 2007, 27(16), 5819-5834. doi: 10.1128/MCB.02422-06 PMID: 17562868
  38. Hoffman, B.; Amanullah, A.; Shafarenko, M.; Liebermann, D.A. The proto-oncogene c-myc in hematopoietic development and leukemogenesis. Oncogene, 2002, 21(21), 3414-3421. doi: 10.1038/sj.onc.1205400 PMID: 12032779
  39. Coller, H.A. Regulation of cell cycle entry and exit: A single cell perspective. Compr. Physiol., 2019, 10(1), 317-344. doi: 10.1002/cphy.c190014 PMID: 31853969

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2023 Bentham Science Publishers