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Erythrose inhibits the progression to invasiveness and reverts drug resistance of cancer stem cells of glioblastoma

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Abstract

Glioblastoma (GBM) is the most frequent brain cancer and more lethal than other cancers. Characteristics of this cancer are its high drug resistance, high recurrence rate and invasiveness. Invasiveness in GBM is related to overexpression of matrix metalloproteinases (MMPs) which are mediated by wnt/β-catenin and induced by the activation of signaling pathways extracellularly activated by the cytokine neuroleukin (NLK) in cancer stem cells (CSC). Therefore, in this work we evaluated the effect of the tetrose saccharide, erythrose (Ery), a NLK inhibitor of invasiveness and drug sensitization in glioblastoma stem cells (GSC). GSC were obtained from parental U373 cell line by a CSC phenotype enrichment protocol based on microenvironmental stress conditions such as hypoxia, hipoglycemia, drug exposition and serum starvation. Enriched fraction of GSC overexpressed the typical markers of brain CSC: low CD133+ and high CD44; in addition, epithelial to mesenchyme transition (EMT) markers and MMPs were increased several times in GSC vs. U373 correlating with higher invasiveness, elongated and tubular mitochondrion and temozolomide (TMZ) resistance. IC50 of Ery was found at nM concentration and at 24 h induced a severe diminution of EMT markers, MMPs and invasiveness in GSC. Furthermore, the phosphorylation pattern of NLK after Ery exposition also was affected. In addition, when Ery was administered to GSC at subIC50, it was capable of reverting TMZ resistance at concentrations innocuous to non-tumor cancer cells. Moreover, Ery added daily induced the death of all GSC. Those findings indicated that the phytodrug Ery could be used as adjuvant therapy in GBM.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CSC:

Cancer stem cells

GBM:

Glioblastoma

GSC:

Glioblastoma cancer stem cells

E4P:

Erythrose 4-phosphate

EMT:

Epithelial-mesenchyme transition

Ery:

Erythrose

HPI/AMF:

Hexose phosphate isomerase/autocrine motility factor

IC50 :

Drug concentration required to inhibit 50% of cellular viability

MMPs:

Matrix metalloproteinases

NLK:

Neuroleukin

P-Ser:

Phosphor-serine

P-Thr:

Phosphor-threonine

TMZ:

Temozolomide

References

  1. Lin D, Wang M, Chen Y, Gong J, Chen L, Shi X, Lan F, Chen Z, Xiong T, Sun H, Wan S. Trends in intracranial glioma incidence and mortality in the United States, 1975–2018. Front Oncol. 2021;11:748061. https://doi.org/10.3389/fonc.2021.748061.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Back MF, Ang EL, Ng WH, See SJ, Lim CC, Chan SP, Yeo TT. Improved median survival for glioblastoma multiforme following introduction of adjuvant temozolomide chemotherapy. Ann Acad Med Singap. 2007;36(5):338–42.

    Article  PubMed  Google Scholar 

  3. Virga J, Szivos L, Hortobágyi T, Chalsaraei MK, Zahuczky G, Steiner L, Tóth J, Reményi-Puskár J, Bognár L, Klekner A. Extracellular matrix differences in glioblastoma patients with different prognoses. Oncol Lett. 2017;17(1):797–806. https://doi.org/10.3892/ol.2018.9649.

    Article  CAS  Google Scholar 

  4. Rong L, Li N, Zhang Z. Emerging therapies for glioblastoma: current state and future directions. J Exp Clin Cancer Res. 2022;41(1):142. https://doi.org/10.1186/s13046-022-02349-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arora A, Somasundaram K. Glioblastoma vs temozolomide: can the red queen race be won? Cancer Biol Ther. 2019;20(8):1083–90. https://doi.org/10.1080/15384047.2019.1599662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7.

    Article  CAS  PubMed  Google Scholar 

  7. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29(12):1203–17. https://doi.org/10.1101/gad.261982.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alfonso J, Talkenberger K, Seifert M, Klink B, Hawkins-Daarud A, Swanson KR, Hatzikirou H, Deutsch A. The biology and mathematical modelling of glioma invasion: a review. J R Soc Interface. 2017;14(136):20170490. https://doi.org/10.1098/rsif.2017.0490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Inoue A, Takahashi H, Harada H, Kohno S, Ohue S, Kobayashi K, Yano H, Tanaka J, Ohnishi T. Cancer stem-like cells of glioblastoma characteristically express MMP-13 and display highly invasive activity. Int J Oncol. 2010;37(5):1121–31. https://doi.org/10.3892/ijo_00000764.

    Article  CAS  PubMed  Google Scholar 

  10. Gonzalez-Avila G, Sommer B, Mendoza-Posada DA, Ramos C, Garcia-Hernandez AA, Falfan-Valencia R. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol Hematol. 2019;137:57–83. https://doi.org/10.1016/j.critrevonc.2019.02.010.

    Article  PubMed  Google Scholar 

  11. Hagemann C, Anacker J, Ernestus RI, Vince GH. A complete compilation of matrix metalloproteinase expression in human malignant gliomas. World J Clin Oncol. 2012;3(5):67–79. https://doi.org/10.5306/wjco.v3.i5.67.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Abdel-Hamid NM, Abass SA. Matrix metalloproteinase contribution in management of cancer proliferation, metastasis and drug targeting. Mol Biol Rep. 2021;48(9):6525–38. https://doi.org/10.1007/s11033-021-06635-z.

    Article  CAS  PubMed  Google Scholar 

  13. Liang W, Chen Y, Li X, Guo F, Sun J, Zhang X, Xu B, Gao W. Label-free proteomic analysis of smoke-drying and shade-drying processes of postharvest rhubarb: a comparative study. Front Plant Sci. 2021;12:663180. https://doi.org/10.3389/fpls.2021.663180.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Niinaka Y, Paku S, Haga A, Watanabe H, Raz A. Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells. Cancer Res. 1998;58(12):2667–74.

    CAS  PubMed  Google Scholar 

  15. Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem. 1991;266(20):13442–8.

    Article  CAS  PubMed  Google Scholar 

  16. Kathagen-Buhmann A, Maire CL, Weller J, Schulte A, Matschke J, Holz M, Ligon KL, Glatzel M, Westphal M, Lamszus K. The secreted glycolytic enzyme GPI/AMF stimulates glioblastoma cell migration and invasion in an autocrine fashion but can have anti-proliferative effects. Neuro Oncol. 2018;20(12):1594–605. https://doi.org/10.1093/neuonc/noy117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gallardo-Pérez JC, Adán-Ladrón de Guevara A, Marín-Hernández A, Moreno-Sánchez R, Rodríguez-Enríquez S. HPI/AMF inhibition halts the development of the aggressive phenotype of breast cancer stem cells. Biochim Biophys Acta Mol Cell Res. 2017;1864(10):1679–90. https://doi.org/10.1016/j.bbamcr.2017.06.015.

    Article  CAS  PubMed  Google Scholar 

  18. Manuel Iglesias J, Beloqui I, Garcia-Garcia F, Leis O, Vazquez-Martin A, Eguiara A, Cufi S, Pavon A, Menendez JA, Dopazo J, Martin AG. Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. PLoS ONE. 2013;8(10):e77281. https://doi.org/10.1371/journal.pone.0077281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gallardo-Pérez JC, Rivero-Segura NA, Marín-Hernández A, Moreno-Sánchez R, Rodríguez-Enríquez S. GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids. Biochim Biophys Acta. 2014;1843(6):1043–53. https://doi.org/10.1016/j.bbamcr.2014.01.013.

    Article  CAS  PubMed  Google Scholar 

  20. Jiménez-García LF, Segura-Valdez ML. Visualizing nuclear structure in situ by atomic force microscopy. Methods Mol Biol. 2004;242:191–9. https://doi.org/10.1385/1-59259-647-9:191.

    Article  PubMed  Google Scholar 

  21. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32(40):4814–24. https://doi.org/10.1038/onc.2012.494.

    Article  CAS  PubMed  Google Scholar 

  22. Liu LL, Yi T, Zhao X. Antitumor effect of d-erythrose in an abdominal metastatic model of colon carcinoma. Oncol Lett. 2015;9(2):769–73. https://doi.org/10.3892/ol.2014.2764.

    Article  PubMed  Google Scholar 

  23. Pandey V, Ranjan N, Narne P, Babu PP. Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis. Sci Rep. 2019;9(1):5012. https://doi.org/10.1038/s41598-019-41380-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oliver L, Lalier L, Salaud C, Heymann D, Cartron PF, Vallette FM. Drug resistance in glioblastoma: are persisters the key to therapy? Cancer Drug Resist. 2020;3(3):287–301. https://doi.org/10.20517/cdr.2020.29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stylli SS. Novel treatment strategies for glioblastoma-a summary. Cancers (Basel). 2021;13(22):5868. https://doi.org/10.3390/cancers13225868.

    Article  PubMed  Google Scholar 

  26. Yusuf S, Aretz P, Nickel AC, Westhoff P, Sharma A, Qin N, Remke M, Steiger HJ, Hänggi D, Liu H, Liu H, Neumann S, Reifenberger G, Maciaczyk J. WNT/β-catenin-mediated resistance to glucose deprivation in glioblastoma stem-like cells. Cancers. 2022;14(13):3165. https://doi.org/10.3390/cancers14133165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166(3):555–66. https://doi.org/10.1016/j.cell.2016.07.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gallardo-Pérez JC, de Guevara AA, García-Amezcua MA, Robledo-Cadena DX, Pacheco-Velázquez SC, Belmont-Díaz JA, Vargas-Navarro JL, Moreno-Sánchez R, Rodríguez-Enríquez S. Celecoxib and dimethylcelecoxib block oxidative phosphorylation, epithelial–mesenchymal transition and invasiveness in breast cancer stem cells. Curr Med Chem. 2022;29(15):2719–35. https://doi.org/10.2174/0929867328666211005124015.

    Article  CAS  PubMed  Google Scholar 

  29. Bordi M, Nazio F, Campello S. The close interconnection between mitochondrial dynamics and mitophagy in cancer. Front Oncol. 2017;7:81. https://doi.org/10.3389/fonc.2017.00081.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang S, Shi X, Wei S, Ma D, Oyinlade O, Lv SQ, Ying M, Zhang YA, Claypool SM, Watkins P, Xia S. Krüppel-like factor 4 (KLF4) induces mitochondrial fusion and increases spare respiratory capacity of human glioblastoma cells. J Biol Chem. 2018;293(17):6544–55. https://doi.org/10.1074/jbc.RA117.001323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. López de Andrés J, Griñán-Lisón C, Jiménez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol. 2020;13(1):136. https://doi.org/10.1186/s13045-020-00966-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li Y, Wei Z, Dong B, Lian Z, Xu Y. Silencing of phosphoglucose isomerase/autocrine motility factor decreases U87 human glioblastoma cell migration. Int J Mol Med. 2016;37(4):998–1004. https://doi.org/10.3892/ijmm.2016.2500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J. 2005;19(11):1422–30. https://doi.org/10.1096/fj.05-3699com.

    Article  CAS  PubMed  Google Scholar 

  34. Kho DH, Zhang T, Balan V, Wang Y, Ha SW, Xie Y, Raz A. Autocrine motility factor modulates EGF-mediated invasion signaling. Can Res. 2014;74(8):2229–37. https://doi.org/10.1158/0008-5472.CAN-13-2937.

    Article  CAS  Google Scholar 

  35. Haga A, Niinaka Y, Raz A. Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein. Biochim Biophys Acta. 2000;1480(1–2):235–44. https://doi.org/10.1016/s0167-4838(00)00075-3.

    Article  CAS  PubMed  Google Scholar 

  36. Funasaka T, Hogan V, Raz A. Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Can Res. 2009;69(13):5349–56. https://doi.org/10.1158/0008-5472.CAN-09-0488.

    Article  CAS  Google Scholar 

  37. Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, Batchelor TT, Bindra RS, Chang SM, Chiocca EA, Cloughesy TF, DeGroot JF, Galanis E, Gilbert MR, Hegi ME, Horbinski C, Huang RY, Lassman AB, Le Rhun E, Lim M, van den Bent MJ. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 2020;22(8):1073–113. https://doi.org/10.1093/neuonc/noaa106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Park HS, Jeoung NH. Autocrine motility factor secreted by HeLa cells inhibits the growth of many cancer cells by regulating AKT/ERK signaling. Biochem Biophys Res Commun. 2020;525(3):557–62. https://doi.org/10.1016/j.bbrc.2020.02.135.

    Article  CAS  PubMed  Google Scholar 

  39. Yang Y, Lian S, Meng L, Qu L, Shou C. Antibody array revealed PRL-3 affects protein phosphorylation and cytokine secretion. PLoS ONE. 2017;12(1):e0169665. https://doi.org/10.1371/journal.pone.0169665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Romagnoli A, Oliverio S, Evangelisti C, Iannicola C, Ippolito G, Piacentini M. Neuroleukin inhibition sensitises neuronal cells to caspase-dependent apoptosis. Biochem Biophys Res Commun. 2003;302(3):448–53. https://doi.org/10.1016/s0006-291x(03)00188-8.

    Article  CAS  PubMed  Google Scholar 

  41. Liudvytska O, Kolodziejczyk-Czepas J. A review on rhubarb-derived substances as modulators of cardiovascular risk factors-a special emphasis on anti-obesity action. Nutrients. 2022;14(10):2053. https://doi.org/10.3390/nu14102053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Talukder AH, Bagheri-Yarmand R, Williams RR, Ragoussis J, Kumar R, Raz A. Antihuman epidermal growth factor receptor 2 antibody herceptin inhibits autocrine motility factor (AMF) expression and potentiates antitumor effects of AMF inhibitors. Clin Cancer Res. 2002;8(10):3285–9. https://doi.org/10.1074/jbc.ra117.001323.

    Article  CAS  PubMed  Google Scholar 

  43. Talukder AH, Adam L, Raz A, Kumar R. Heregulin regulation of autocrine motility factor expression in human tumor cells. Cancer Res. 2000;60(2):474–80.

    CAS  PubMed  Google Scholar 

  44. Haga A, Funasaka T, Niinaka Y, Raz A, Nagase H. Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression. Int J Cancer. 2003;107(5):707–14. https://doi.org/10.1002/ijc.11449.

    Article  CAS  PubMed  Google Scholar 

  45. Trejo-Solís C, Serrano-Garcia N, Escamilla-Ramírez Á, Castillo-Rodríguez RA, Jimenez-Farfan D, Palencia G, Calvillo M, Alvarez-Lemus MA, Flores-Nájera A, Cruz-Salgado A, Sotelo J. Autophagic and apoptotic pathways as targets for chemotherapy in glioblastoma. Int J Mol Sci. 2018;19(12):3773. https://doi.org/10.3390/ijms19123773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The present work was partially supported by grants from CONACyT-México (No. 243249 to JCGP). Authors want to thanks to students Monserrat Vazquez-Bautista, Erika Montserrat Navarro-Araujo and Andrea Torrero-Díaz for their technical assistance.

Funding

The present work was partially supported by Grants from CONACyT-México (No. 243249 to JCGP).

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Authors and Affiliations

  1. Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología, “Ignacio Chávez”, Juan Badiano No. 1. Col Sección XVI, Tlalpan, Mexico City, Mexico

    Juan Carlos Gallardo-Pérez & Laura Gabriela Sánchez-Lozada

  2. Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico

    María Cristina Trejo-Solís

  3. Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico City, Mexico

    Diana Xochiquetzal Robledo-Cadena

  4. Departamento de Fisiología, Instituto Nacional de Cardiología, Mexico City, Mexico

    Rebeca López-Marure

  5. Departamento de Biología Celular, Facultad de Ciencias, UNAM, Mexico City, Mexico

    Lourdes Teresa Agredano-Moreno & Luis Felipe Jimenez-García

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  1. Juan Carlos Gallardo-Pérez
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  2. María Cristina Trejo-Solís
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  7. Laura Gabriela Sánchez-Lozada
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [JCGP], [MCTS], [LTAM], [RLM], [LFJG] and [DXRC]. The first draft of the manuscript was written by [JCGP] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Juan Carlos Gallardo-Pérez.

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Gallardo-Pérez, J.C., Trejo-Solís, M.C., Robledo-Cadena, D.X. et al. Erythrose inhibits the progression to invasiveness and reverts drug resistance of cancer stem cells of glioblastoma. Med Oncol 40, 104 (2023). https://doi.org/10.1007/s12032-023-01969-z

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