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Caspase-9-mediated cleavage of vimentin attenuates the aggressiveness of leukemic NB4 cells

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A Correction to this article was published on 04 April 2023

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Abstract

Vimentin is a main type 3 intermediate filament protein. It seems that abnormal expression of vimentin is contributed to the appearance of the aggressive feature of cancer cells. So that it has been reported that malignancy and epithelial–mesenchymal transition in solid tumors, and poor clinical outcomes in patients with lymphocytic leukemia and acute myelocytic leukemia have been associated with the high expression of vimentin. Vimentin is a non-caspase substrate of caspase-9 although its cleavage by caspase-9 in biological processes has not been reported. In the present study, we sought to understand whether vimentin cleavage mediated by caspase-9 could reverse the malignancy in leukemic cells. Herein, to address the issue, we investigated vimentin changes in differentiation and took advantage of the inducible caspase-9 (iC9)/AP1903 system in human leukemic NB4 cells. Following the transfection and treatment of the cells using the iC9/AP1903 system, vimentin expression, cleavage, and subsequently, the cell invasion and the relevant markers such as CD44 and MMP-9 were evaluated. Our results revealed the downregulation and cleavage of vimentin which attenuates the malignant phenotype of the NB4 cells. Considering the favorable effect of this strategy in keeping down the malignant features of the leukemic cells, the effect of the iC9/AP1903 system in combination with all-trans-retinoic acid (ATRA) treatment was evaluated. The obtained data prove that iC9/AP1903 significantly makes the leukemic cells more sensitive to ATRA.

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References

  1. Morishima N (1999) Changes in nuclear morphology during apoptosis correlate with vimentin cleavage by different caspases located either upstream or downstream of Bcl-2 action. Genes Cells 4:401–414

    Article  CAS  PubMed  Google Scholar 

  2. Nakanishi K, Maruyama M, Shibata T, Morishima N (2001) Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. J Biol Chem 276:41237–41244

    Article  CAS  PubMed  Google Scholar 

  3. Ivaska J, Pallari H-M, Nevo J, Eriksson JE (2007) Novel functions of vimentin in cell adhesion, migration, and signaling. Exp Cell Res 313:2050–2062

    Article  CAS  PubMed  Google Scholar 

  4. Nieminen M, Henttinen T, Merinen M, Marttila-Ichihara F, Eriksson JE, Jalkanen S (2006) Vimentin function in lymphocyte adhesion and transcellular migration. Nat Cell Biol 8:156–162

    Article  CAS  PubMed  Google Scholar 

  5. Herrmann H, Fouquet B, Franke WW (1989) Expression of intermediate filament proteins during development of Xenopus laevis. I. cDNA clones encoding different forms of vimentin. Development 105:279–298

    Article  CAS  PubMed  Google Scholar 

  6. Yi YY, Yi J, Zhu X, Zhang J, Zhou J, Tang X, Lin J, Wang P, Deng ZQ (2019) Circular RNA of vimentin expression as a valuable predictor for acute myeloid leukemia development and prognosis. J Cell Physiol 234:3711–3719

    Article  CAS  PubMed  Google Scholar 

  7. Zhang M-H, Lee J-S, Kim H-J, Jin D-I, Kim J-I, Lee K-J, Seo J-S (2006) HSP90 protects apoptotic cleavage of vimentin in geldanamycin-induced apoptosis. Mol Cell Biochem 281:111–121

    Article  CAS  PubMed  Google Scholar 

  8. Ribatti D, Tamma R, Annese T (2020) Epithelial-mesenchymal transition in cancer: a historical overview. Transl Oncol 13:100773. https://doi.org/10.1016/j.tranon.2020.100773

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kalluri R, Weinberg RA (2010) Erratum: The basics of epithelial-mesenchymal transition (J Clin Investig (2009) 119(6): 1420–1428). J Clin Investig 120:1786

  10. Satelli A, Li S (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 68:3033–3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wu S, Du Y, Beckford J, Alachkar H (2018) Upregulation of the EMT marker vimentin is associated with poor clinical outcome in acute myeloid leukemia. J Transl Med 16:170. https://doi.org/10.1186/s12967-018-1539-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu S, Du Y, Beckford J, Alachkar H (2018) Upregulation of the EMT marker vimentin is associated with poor clinical outcome in acute myeloid leukemia. J Transl Med 16:1–9

    Article  Google Scholar 

  13. Bratton DL, Fadok VA, Richter DA, Kailey JM, Frasch SC, Nakamura T, Henson PM (1999) Polyamine regulation of plasma membrane phospholipid flip-flop during apoptosis. J Biol Chem 274:28113–28120

    Article  CAS  PubMed  Google Scholar 

  14. Yang L, Zhao H, Li S-W, Ahrens K, Collins C, Eckenrode S, Ruan Q-g, McIndoe RA, She J-X (2003) Gene expression profiling during all-trans retinoic acid-induced cell differentiation of acute promyelocytic leukemia cells. J Mol Diagn 5:212–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jasek E, Mirecka J, Litwin JA (2008) Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate) on drug sensitivity of HL60 and NB4 cells in vitro. Folia Histochem Cytobiol 46:323–330

    Article  CAS  PubMed  Google Scholar 

  16. Sordet O, Rébé C, Plenchette S, Zermati Y, Hermine O, Vainchenker W, Garrido C, Solary E, Dubrez-Daloz L (2002) Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood J Am Soc Hematol 100:4446–4453

    CAS  Google Scholar 

  17. Balvan J, Krizova A, Gumulec J, Raudenska M, Sladek Z, Sedlackova M, Babula P, Sztalmachova M, Kizek R, Chmelik R (2015) Multimodal holographic microscopy: distinction between apoptosis and oncosis. PLoS ONE 10:e0121674

    Article  PubMed  PubMed Central  Google Scholar 

  18. Madadi Z, Akbari-Birgani S, Monfared PD, Mohammadi S (2019) The non-apoptotic role of caspase-9 promotes differentiation in leukemic cells. Biochim Biophys Acta (BBA)-Mol Cell Res 1866:118524

    Article  CAS  Google Scholar 

  19. Cao Y, Wang F, Liu H-Y, Fu Z-D, Han R (2005) Resveratrol induces apoptosis and differentiation in acute promyelocytic leukemia (NB4) cells. J Asian Nat Prod Res 7:633–641

    Article  CAS  PubMed  Google Scholar 

  20. Trochon V, Mabilat C, Bertrand P, Legrand Y, Smadja-Joffe F, Soria C, Delpech B, Lu H (1996) Evidence of involvement of CD44 in endothelial cell proliferation, migration and angiogenesis in vitro. Int J Cancer 66:664–668

    Article  CAS  PubMed  Google Scholar 

  21. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    Article  CAS  PubMed  Google Scholar 

  22. Duprez E, Ruchaud S, Houge G, Martin-Thouvenin V, Valensi F, Kastner P, Berger R, Lanotte M (1992) A retinoid acid’resistant’t (15; 17) acute promyelocytic leukemia cell line: isolation, morphological, immunological, and molecular features. Leukemia 6:1281–1287

    CAS  PubMed  Google Scholar 

  23. Gallagher RE, Moser BK, Racevskis J, Poiré X, Bloomfield CD, Carroll AJ, Ketterling RP, Roulston D, Schachter-Tokarz E, Zhou D-c (2012) Treatment-influenced associations of PML-RAR α mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. Blood J Am Soc Hematol 120:2098–2108

    CAS  Google Scholar 

  24. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713–1722

    Article  CAS  PubMed  Google Scholar 

  25. Song W, Dong Z, Jin T, Mantellini MG, Núñez G, Nör JE (2008) Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells. Cancer Gene Ther 15:667–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Madadi Z, Akbari-Birgani S, Mohammadi S, Khademy M, Mousavi SA (2021) The effect of caspase-9 in the differentiation of SH-SY5Y cells. Eur J Pharmacol 904:174138

    Article  CAS  PubMed  Google Scholar 

  27. Abe T, Takano K, Suzuki A, Shimada Y, Inagaki M, Sato N, Obinata T, Endo T (2004) Myocyte differentiation generates nuclear invaginations traversed by myofibrils associating with sarcomeric protein mRNAs. J Cell Sci 117:6523–6534

    Article  CAS  PubMed  Google Scholar 

  28. Sarria AJ, Lieber JG, Nordeen SK, Evans RM (1994) The presence or absence of a vimentin-type intermediate filament network affects the shape of the nucleus in human SW-13 cells. J Cell Sci 107:1593–1607

    Article  CAS  PubMed  Google Scholar 

  29. Mendez MG, Kojima SI, Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24:1838–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brzozowa M, Wyrobiec G, Kołodziej I, Sitarski M, Matysiak N, Reichman-Warmusz E, Żaba M, Wojnicz R (2015) The aberrant overexpression of vimentin is linked to a more aggressive status in tumours of the gastrointestinal tract. Przeglad gastroenterologiczny 10:7

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu S, Liu L, Ye W, Ye D, Wang T, Guo W, Liao Y, Xu D, Song H, Zhang L (2016) High vimentin expression associated with lymph node metastasis and predicated a poor prognosis in oral squamous cell carcinoma. Sci Rep 6:1–9

    Google Scholar 

  32. Xu H, Tian Y, Yuan X, Wu H, Liu Q, Pestell RG, Wu K (2015) The role of CD44 in epithelial–mesenchymal transition and cancer development. Onco Targets Ther 8:3783

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cho SH, Park YS, Kim HJ, Kim CH, Lim SW, Huh JW, Lee JH, Kim HR (2012) CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion. Int J Oncol 41:211–218

    CAS  PubMed  Google Scholar 

  34. Li Y, He J, Wang F, Wang X, Yang F, Zhao C, Feng C, Li T (2020) Role of MMP-9 in epithelial-mesenchymal transition of thyroid cancer. World J Surg Oncol 18:1–9

    Article  CAS  Google Scholar 

  35. Lin CY, Tsai PH, Kandaswami CC, Lee PP, Huang CJ, Hwang JJ, Lee MT (2011) Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial–mesenchymal transition. Cancer Sci 102:815–827

    Article  CAS  PubMed  Google Scholar 

  36. Li S, Luo W (2019) Matrix metalloproteinase 2 contributes to aggressive phenotype, epithelial-mesenchymal transition and poor outcome in nasopharyngeal carcinoma. Onco Targets Ther 12:5701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hamid O, Robert C, Daud A, Hodi FS, Hwu W-J, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS (2013) Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med 369:134–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim JH, Kim JH, Cho CS, Jun HO, Kim DH, Yu YS, Kim K-W (2010) Differential roles of matrix metalloproteinase-9 and-2, depending on proliferation or differentiation of retinoblastoma cells. Invest Ophthalmol Vis Sci 51:1783–1788

    Article  PubMed  Google Scholar 

  39. Arai Y, Park S, Choi B, Ko K-W, Choi WC, Lee J-M, Han D-W, Park H-K, Han I, Lee JH (2016) Enhancement of matrix metalloproteinase-2 (MMP-2) as a potential chondrogenic marker during chondrogenic differentiation of human adipose-derived stem cells. Int J Mol Sci 17:963

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cui J, Gong M, He Y, Li Q, He T, Bi Y (2016) All-trans retinoic acid inhibits proliferation, migration, invasion and induces differentiation of hepa1-6 cells through reversing EMT in vitro. Int J Oncol 48:349–357. https://doi.org/10.3892/ijo.2015.3235

    Article  CAS  PubMed  Google Scholar 

  41. Shi G, Zheng X, Wu X, Wang S, Wang Y, Xing F (2019) All-trans retinoic acid reverses epithelial-mesenchymal transition in paclitaxel-resistant cells by inhibiting nuclear factor kappa B and upregulating gap junctions. Cancer Sci 110:379–388. https://doi.org/10.1111/cas.13855

    Article  CAS  PubMed  Google Scholar 

  42. Kahlert UD, Joseph JV, Kruyt FA (2017) EMT-and MET-related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities. Mol Oncol 11:860–877

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported and funded by the Institute for Advanced Studies in Basic Sciences (IASBS) and Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran

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Authors and Affiliations

  1. Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), 45137-66731, Zanjan, Iran

    Fatemeh Hakim & Shiva Akbari-Birgani

  2. Laboratory for Functional and Metabolic Imaging, Institute of Physics, Swiss Federal Institute of Technology (EPFL), Station6, 1015, Lausanne, Switzerland

    Cyrus Kazemiraad

  3. Research Center for Basic Sciences and Modern Technologies (RBST), Institute for Advanced Studies in Basic Sciences (IASBS), 45137-66731, Zanjan, Iran

    Shiva Akbari-Birgani

  4. Department of Physics, Institute for Advanced Studies in Basic Sciences (IASBS), 45137-66731, Zanjan, Iran

    Daryoush Abdollahpour

  5. Optics Research Center, Institute for Advanced Studies in Basic Sciences (IASBS), 45137-66731, Zanjan, Iran

    Daryoush Abdollahpour

  6. Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran

    Saeed Mohammadi

  7. Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Saeed Mohammadi

  8. Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Saeed Mohammadi

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  1. Fatemeh Hakim
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Contributions

The research was supervised by SA-B and SM. The research conducted by FH and CK. Interpretation of the data were done by SA-B and DA. Funding was exquisite by SA-B and SM. Writing and reviewing of manuscript were performed by SA-B and SM and edited by SAM.

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Correspondence to Shiva Akbari-Birgani or Saeed Mohammadi.

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Hakim, F., Kazemiraad, C., Akbari-Birgani, S. et al. Caspase-9-mediated cleavage of vimentin attenuates the aggressiveness of leukemic NB4 cells. Mol Cell Biochem 478, 2435–2444 (2023). https://doi.org/10.1007/s11010-023-04671-w

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