Advertisement

Biochemistry (Moscow)

, Volume 84, Issue 11, pp 1424–1432 | Cite as

Effect of Chemotherapeutic Agents on the Expression of Retinoid Receptors and Markers of Cancer Stem Cells and Epithelial-Mesenchymal Transition

  • O. Isayev
  • Y. Zhu
  • E. Gasimov
  • J. Werner
  • A. V. BazhinEmail author
Article

Abstract

A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents — gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRβ in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.

Keywords

pancreatic ductal adenocarcinoma cancer stem cells epithelial-mesenchymal transition retinoid receptors 

Abbriviation

CSC

cancer stem cell

EMT

epithelial-mesenchymal transition

5-FU

5-fluorouracil

gem

gemcitabine

PDAC

pancreatic ductal adenocarcinoma

RAR

retinoic acid receptor

RXR

retinoid X receptor

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

We thank Ms. Michaela Svihla and Mr. Tommi Bauer for their excellent technical assistance and Dr. Mara Taverna for her administrative assistance.

References

  1. 1.
    Werner, J., Combs, S. E., Springfeld, C., Hartwig, W., Hackert, T., and Buchler, M. W. (2013) Advanced-stage pancreatic cancer: therapy options, Nat. Rev. Clin. Oncol., 10, 323–333.CrossRefGoogle Scholar
  2. 2.
    Hartwig, W., Werner, J., Jager, D., Debus, J., and Buchler, M. W. (2013) Improvement of surgical results for pancreatic cancer, Lancet Oncol., 14, e476–e485.CrossRefGoogle Scholar
  3. 3.
    Burris, H. A., 3rd, Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M. R., Cripps, M. C., Portenoy, R. K., Storniolo, A. M., Tarassoff, P., Nelson, R., Dorr, F. A., Stephens, C. D., and Von Hoff, D. D. (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, J. Clin. Oncol., 15, 2403–2413.CrossRefGoogle Scholar
  4. 4.
    Pusceddu, S., Ghidini, M., Torchio, M., Corti, F., Tomasello, G., Niger, M., Prinzi, N., Nichetti, F., Coinu, A., Di Bartolomeo, M., Cabiddu, M., Passalacqua, R., de Braud, F., and Petrelli, F. (2019) Comparative effectiveness of gemcitabine plus nab-paclitaxel and FOLFIRINOX in the first-line setting of metastatic pancreatic cancer: a systematic review and meta-analysis, Cancers (Basel), 11, E484, doi:  https://doi.org/10.3390/cancers11040484.CrossRefGoogle Scholar
  5. 5.
    Shevchenko, I., Karakhanova, S., Soltek, S., Link, J., Bayry, J., Werner, J., Umansky, V., and Bazhin, A. V. (2013) Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer, Int. J. Cancer, 133, 98–107.CrossRefGoogle Scholar
  6. 6.
    Karakhanova, S., Mosl, B., Harig, S., von Ahn, K., Fritz, J., Schmidt, J., Jager, D., Werner, J., and Bazhin, A. V. (2014) Influence of interferon-alpha combined with chemo(radio)therapy on immunological parameters in pancreatic adenocarcinoma, Int. J. Mol. Sci., 15, 4104–4125.CrossRefGoogle Scholar
  7. 7.
    Fritz, J., Karakhanova, S., Brecht, R., Nachtigall, I., Werner, J., and Bazhin, A. V. (2015) In vitro immunomodulatory properties of gemcitabine alone and in combination with interferon-alpha, Immunol. Lett., 168, 111–119.CrossRefGoogle Scholar
  8. 8.
    Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation, Cell, 144, 646–674.CrossRefGoogle Scholar
  9. 9.
    Tirino, V., Desiderio, V., Paino, F., De Rosa, A., Papaccio, F., La Noce, M., Laino, L., De Francesco, F., and Papaccio, G. (2013) Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization, FASEB J., 27, 13–24.CrossRefGoogle Scholar
  10. 10.
    Zhu, Y., Karakhanova, S., Huang, X., Deng, S. P., Werner, J., and Bazhin, A. V. (2014) Influence of interferon-alpha on the expression of the cancer stem cell markers in pancreatic carcinoma cells, Exp. Cell Res., 324, 146–156.CrossRefGoogle Scholar
  11. 11.
    Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., Reichert, M., Beatty, G. L., Rustgi, A. K., Vonderheide, R. H., Leach, S. D., and Stanger, B. Z. (2012) EMT and dissemination precede pancreatic tumor formation, Cell, 148, 349–361.CrossRefGoogle Scholar
  12. 12.
    Amann, P. M., Eichmuller, S. B., Schmidt, J., and Bazhin, A. V. (2011) Regulation of gene expression by retinoids, Curr. Med. Chem., 18, 1405–1412.CrossRefGoogle Scholar
  13. 13.
    Bleul, T., Ruhl, R., Bulashevska, S., Karakhanova, S., Werner, J., and Bazhin, A. V. (2015) Reduced retinoids and retinoid receptors’ expression in pancreatic cancer: a link to patient survival, Mol. Carcinog., 54, 870–879.CrossRefGoogle Scholar
  14. 14.
    Bazhin, A. V., Bleul, T., de Lera, A. R., Werner, J., and Ruhl, R. (2016) Relationship between all-trans-13,14-dihydroretinoic acid and pancreatic adenocarcinoma, Pancreas, 45, e29–e31.CrossRefGoogle Scholar
  15. 15.
    Martins-Neves, S. R., Cleton-Jansen, A. M., and Gomes, C. M. F. (2018) Therapy-induced enrichment of cancer stem-like cells in solid human tumors: where do we stand? Pharmacol. Res., 137, 193–204.CrossRefGoogle Scholar
  16. 16.
    Bulle, A., Dekervel, J., Libbrecht, L., Nittner, D., Deschuttere, L., Lambrecht, D., Van Cutsem, E., Verslype, C., and van Pelt, J. (2019) Gemcitabine induces epithelial-to-mesenchymal transition in patient-derived pancreatic ductal adenocarcinoma xenografts, Am. J. Transl. Res., 11, 765–779.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Quan, Q., Zhong, F., Wang, X., Guo, L., and Chen, K. (2019) PAR2 inhibition enhanced the sensitivity of colorectal cancer cells to 5-FU and reduced EMT signaling, Oncol. Res., 27, 779–788, doi:  https://doi.org/10.3727/096504018X15442985680348.CrossRefGoogle Scholar
  18. 18.
    Bazhin, A. V., Tambor, V., Dikov, B., Philippov, P. P., Schadendorf, D., and Eichmuller, S. B. (2010) cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca(2+) homeostasis in melanoma cells, Cell. Mol. Life Sci., 67, 817–828.CrossRefGoogle Scholar
  19. 19.
    Schmittgen, T. D., and Livak, K. J. (2008) Analyzing real-time PCR data by the comparative C(T) method, Nat. Protoc., 3, 1101–1108.CrossRefGoogle Scholar
  20. 20.
    Diab, M., Azmi, A., Mohammad, R., and Philip, P. A. (2019) Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges, Expert. Opin. Pharmacother., 20, 535–546.CrossRefGoogle Scholar
  21. 21.
    Chen, W. H., Horoszewicz, J. S., Leong, S. S., Shimano, T., Penetrante, R., Sanders, W. H., Berjian, R., Douglass, H. O., Martin, E. W., and Chu, T. M. (1982) Human pancreatic adenocarcinoma: in vitro and in vivo morphology of a new tumor line established from ascites, In vitro, 18, 24–34.CrossRefGoogle Scholar
  22. 22.
    Sipos, B., Moser, S., Kalthoff, H., Torok, V., Lohr, M., and Kloppel, G. (2003) A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform, Virchows Arch., 442, 444–452.PubMedGoogle Scholar
  23. 23.
    Kim, S. K., Kim, H., Lee, D. H., Kim, T. S., Kim, T., Chung, C., Koh, G. Y., Kim, H., and Lim, D. S. (2013) Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells, PLoS One, 8, e78130.CrossRefGoogle Scholar
  24. 24.
    Was, H., Czarnecka, J., Kominek, A., Barszcz, K., Bernas, T., Piwocka, K., and Kaminska, B. (2018) Some chemotherapeutics-treated colon cancer cells display a specific phenotype being a combination of stem-like and senescent cell features, Cancer Biol. Ther., 19, 63–75.CrossRefGoogle Scholar
  25. 25.
    Arumugam, T., Ramachandran, V., Fournier, K. F., Wang, H., Marquis, L., Abbruzzese, J. L., Gallick, G. E., Logsdon, C. D., McConkey, D. J., and Choi, W. (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer, Cancer Res., 69, 5820–5828.CrossRefGoogle Scholar
  26. 26.
    Zheng, X., Carstens, J. L., Kim, J., Scheible, M., Kaye, J., Sugimoto, H., Wu, C. C., LeBleu, V. S., and Kalluri, R. (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer, Nature, 527, 525–530.CrossRefGoogle Scholar
  27. 27.
    Zhang, W., Feng, M., Zheng, G., Chen, Y., Wang, X., Pen, B., Yin, J., Yu, Y., and He, Z. (2012) Chemoresistance to 5-fluorouracil induces epithelial-mesenchymal transition via up-regulation of Snail in MCF7 human breast cancer cells, Biochem. Biophys. Res. Commun., 417, 679–685.CrossRefGoogle Scholar
  28. 28.
    Wu, Q., Wang, R., Yang, Q., Hou, X., Chen, S., Hou, Y., Chen, C., Yang, Y., Miele, L., Sarkar, F. H., Chen, Y., and Wang, Z. (2013) Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway, Oncotarget, 4, 1999–2009.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Druzhkova, I., Ignatova, N., Prodanets, N., Kiselev, N., Zhukov, I., Shirmanova, M., Zagainov, V., and Zagaynova, E. (2019) E-cadherin in colorectal cancer: relation to chemosensitivity, Clin. Colorectal Cancer, 18, e74–e86.CrossRefGoogle Scholar
  30. 30.
    Wang, R., Cheng, L., Xia, J., Wang, Z., Wu, Q., and Wang, Z. (2014) Gemcitabine resistance is associated with epithelial-mesenchymal transition and induction of HIF-1alpha in pancreatic cancer cells, Curr. Cancer Drug Targets, 14, 407–417.CrossRefGoogle Scholar
  31. 31.
    Tooker, P., Yen, W. C., Ng, S. C., Negro-Vilar, A., and Hermann, T. W. (2007) Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification, Cancer Res., 67, 4425–4433.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • O. Isayev
    • 1
    • 2
  • Y. Zhu
    • 3
  • E. Gasimov
    • 1
  • J. Werner
    • 4
  • A. V. Bazhin
    • 4
    Email author
  1. 1.Department of Histology, Embryology and CytologyAzerbaijan Medical UniversityBakuAzerbaijan
  2. 2.Genetic Resources InstituteAzerbaijan National Academy of SciencesBakuAzerbaijan
  3. 3.Department of Oncology, Henan University Huaihe HospitalInternational Joint Laboratory for Cell Medical Engineering of Henan ProvinceKaifeng, HenanPeople’s Republic of China
  4. 4.Department of General, Visceral, and Transplantation SurgeryLudwig-Maximilians-University MunichMunichGermany

Personalised recommendations