Skip to main content
SpringerLink
Log in

CD133 suppression increases the sensitivity of prostate cancer cells to paclitaxel

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

One of the major barriers in cancer therapy is the resistance to conventional therapies and cancer stem cells (CSCs) are among the main causes of this problem. CD133 as a CSC marker displays stem cell-like properties, tumorigenic capacity, and drug resistance in various cancers. However, the molecular mechanism behind CD133 function in prostate cancer (PC) still remains unclear. This research aimed to illustrate the probabilistic mechanism of CD133-siRNA and paclitaxel in the reduction of chemoresistance in PC cells. To measure the cell viability, migratory capacity, CSCs properties, invasive potential, apoptosis and cell cycle progression of the cells, the MTT, wound healing, spheroid assay, colony formation assay, DAPI staining and flow cytometry assays were applied in the LNCaP cell line, respectively. Also, quantitative real-time PCR (qRT-PCR) and western blot method were used for measuring the expression of CD133 and the effects of CD133 silencing on the AKT/mTOR/c-myc axis and pro-metastatic genes expression. We showed that the CD133-siRNA considerably decreased the CD133 expression. Moreover, CD133-siRNA and paclitaxel treatment significantly decreased cell proliferation and also inhibited the ability of cell migration and invasion and reduced pro-metastatic genes expression. Additionally, we found that the simultaneous use of CD133-siRNA and paclitaxel increased the paclitaxel‐induced apoptosis. Our results confirmed that CD133 silencing combined with paclitaxel synergistically could suppress cell migration, invasion, and proliferation and enhance the chemosensitivity compared with mono treatment. Therefore, CD133 silencing therapy could be viewed as a promising and efficient strategy in PC targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  Google Scholar 

  2. Divrik RT, Türkeri L, Şahin AF et al (2012) Prediction of response to androgen deprivation therapy and castration resistance in primary metastatic prostate cancer. Urol Int 88:25–33. https://doi.org/10.1159/000334539

    Article  CAS  PubMed  Google Scholar 

  3. Erdogan S, Turkekul K, Dibirdik I et al (2019) Midkine silencing enhances the anti–prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB. Invest New Drugs. https://doi.org/10.1007/s10637-019-00774-8

    Article  PubMed  Google Scholar 

  4. Ni J, Cozzi P, Hao J et al (2014) Cancer stem cells in prostate cancer chemoresistance. Curr Cancer Drug Targets 14:225–240. https://doi.org/10.2174/1568009614666140328152459

    Article  CAS  PubMed  Google Scholar 

  5. Shiozawa Y, Berry JE, Eber MR et al (2016) The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget 7:41217–41232. https://doi.org/10.18632/oncotarget.9251

    Article  PubMed  PubMed Central  Google Scholar 

  6. Harris KS, Kerr BA (2017) Prostate cancer stem cell markers drive progression, therapeutic resistance, and bone metastasis. Stem Cells Int. https://doi.org/10.1155/2017/8629234

    Article  PubMed  PubMed Central  Google Scholar 

  7. Aghajani M, Mansoori B, Mohammadi A et al (2019) New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation. J Cell Physiol 234:21642–21661. https://doi.org/10.1002/jcp.28824

    Article  CAS  PubMed  Google Scholar 

  8. Chang HH, Chen BY, Wu CY et al (2011) Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. J Biomed Sci 18:6. https://doi.org/10.1186/1423-0127-18-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jang JW, Song Y, Kim SH et al (2017) CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma. Cancer Lett 389:1–10. https://doi.org/10.1016/j.canlet.2016.12.023

    Article  CAS  PubMed  Google Scholar 

  10. Burnett JC, Rossi JJ, Tiemann K (2011) Current progress of siRNA/shRNA therapeutics in clinical trials. Biotechnol J 6:1130–1146. https://doi.org/10.1002/biot.201100054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fire AZ (2007) Gene silencing by double-stranded RNA (Nobel Lecture). Angew Chemie Int Ed 46:6966–6984. https://doi.org/10.1002/anie.200701979

    Article  CAS  Google Scholar 

  12. Mansoori B, Mohammadi A, Goldar S et al (2016) Silencing of high mobility group isoform I-C (HMGI-C) enhances paclitaxel chemosensitivity in breast adenocarcinoma cells (MDAMB-468). Adv Pharm Bull 6:171–177. https://doi.org/10.15171/apb.2016.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mansoori B, Shotorbani SS, Baradaran B (2014) RNA interference and its role in cancer therapy. Adv Pharm Bull 4:313–321. https://doi.org/10.5681/apb.2014.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shajari N, Mansoori B, Davudian S et al (2017) Overcoming the challenges of siRNA delivery: nanoparticle strategies. Curr Drug Deliv 14:36–46. https://doi.org/10.2174/1567201813666160816105408

    Article  CAS  PubMed  Google Scholar 

  15. Ojo D, Lin X, Wong N et al (2015) Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer. Cancers (Basel) 7:2290–2308. https://doi.org/10.3390/cancers7040890

    Article  CAS  Google Scholar 

  16. Collins AT, Berry PA, Hyde C et al (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951. https://doi.org/10.1158/0008-5472.CAN-05-2018

    Article  CAS  PubMed  Google Scholar 

  17. Maitland NJ, Collins A (2005) A tumour stem cell hypothesis for the origins of prostate cancer. BJU Int 96:1219–1223. https://doi.org/10.1111/j.1464-410X.2005.05744.x

    Article  CAS  PubMed  Google Scholar 

  18. Vander Griend DJ, Karthaus WL, Dalrymple S et al (2008) The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res 68:9703–9711. https://doi.org/10.1158/0008-5472.CAN-08-3084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Glumac PM, LeBeau AM (2018) The role of CD133 in cancer: a concise review. Clin Transl Med 7:1–14. https://doi.org/10.1186/s40169-018-0198-1

    Article  Google Scholar 

  20. Richardson GD, Robson CN, Lang SH et al (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117:3539–3545. https://doi.org/10.1242/jcs.01222

    Article  CAS  PubMed  Google Scholar 

  21. Reyes EE, Kunovac SK, Duggan R et al (2013) Growth kinetics of CD133-positive prostate cancer cells. Prostate 73:724–733. https://doi.org/10.1002/pros.22616

    Article  CAS  PubMed  Google Scholar 

  22. Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55. https://doi.org/10.1016/0065-2571(84)90007-4

    Article  CAS  PubMed  Google Scholar 

  23. Reyes EE, Gillard M, Duggan R, et al (2015) Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J Transl Sci 1:https://oatext.com/Molecular-analysis-of-CD133-posi

  24. Reyes EE, Vander Weele DJ, Isikbay M et al (2014) Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J Transl Med 12:1–15. https://doi.org/10.1186/s12967-014-0313-z

    Article  CAS  Google Scholar 

  25. Angelastro JM, Lame MW (2010) Overexpression of CD133 promotes drug resistance in C6 glioma cells. Mol Cancer Res 8:1105–1115. https://doi.org/10.1158/1541-7786.MCR-09-0383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li K, Li X, Tian J et al (2016) Downregulation of DNA-PKcs suppresses P-gp expression via inhibition of the Akt/NF-κB pathway in CD133-positive osteosarcoma MG-63 cells. Oncol Rep 36:1973–1980. https://doi.org/10.3892/or.2016.4991

    Article  CAS  PubMed  Google Scholar 

  27. El-Khattouti A, Selimovic D, Haïkel Y et al (2014) Identification and analysis of CD133+ melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response. Cancer Lett 343:123–133. https://doi.org/10.1016/j.canlet.2013.09.024

    Article  CAS  PubMed  Google Scholar 

  28. Zhu Y, Yu J, Wang S et al (2014) Overexpression of CD133 enhances chemoresistance to 5-fluorouracil by activating the PI3K/Akt/p70S6K pathway in gastric cancer cells. Oncol Rep 32:2437–2444. https://doi.org/10.3892/or.2014.3488

    Article  CAS  PubMed  Google Scholar 

  29. Song S, Pei G, Du Y et al (2018) Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells. Am J Transl Res 10:304–314

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rappa G, Fodstad O, Lorico A (2008) The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells 26:3008–3017. https://doi.org/10.1634/stemcells.2008-0601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Elsaba TMA, Martinez-Pomares L, Robins AR et al (2010) The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer. PLoS ONE. https://doi.org/10.1371/journal.pone.0010714

    Article  PubMed  PubMed Central  Google Scholar 

  32. Horst D, Scheel SK, Liebmann S et al (2009) The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol 219:427–434. https://doi.org/10.1002/path.2597

    Article  CAS  PubMed  Google Scholar 

  33. Morgia G, Falsaperla M, Malaponte G et al (2005) Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res 33:44–50. https://doi.org/10.1007/s00240-004-0440-8

    Article  CAS  PubMed  Google Scholar 

  34. Chinni SR, Sivalogan S, Dong Z et al (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: The role of bone microenvironment-associated CXCL12. Prostate 66:32–48. https://doi.org/10.1002/pros.20318

    Article  CAS  PubMed  Google Scholar 

  35. Yang B, Tang F, Zhang B et al (2014) Matrix metalloproteinase-9 overexpression is closely related to poor prognosis in patients with colon cancer. World J Surg Oncol 12:1–6. https://doi.org/10.1186/1477-7819-12-24

    Article  Google Scholar 

  36. Piotrowski-Daspit AS, Tien J, Nelson CM (2016) Interstitial fluid pressure regulates collective invasion in engineered human breast tumors via Snail, vimentin, and E-cadherin. Integr Biol 8:319–331. https://doi.org/10.1039/c5ib00282f

    Article  CAS  Google Scholar 

  37. Chang L, Graham PH, Hao J et al (2013) Acquisition of epithelialmesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. https://doi.org/10.1038/cddis.2013.407

    Article  PubMed  PubMed Central  Google Scholar 

  38. Edlind MP, Hsieh AC (2014) PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl 16:378–386. https://doi.org/10.4103/1008-682X.122876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. LoRusso PM (2016) Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol 34:3803–3815. https://doi.org/10.1200/JCO.2014.59.0018

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ibanez E, Agliano A, Prior C et al (2012) The quinoline imidoselenocarbamate EI201 blocks the AKT/mTOR pathway and targets cancer stem cells leading to a strong antitumor activity. Curr Med Chem 19:3031–3043. https://doi.org/10.2174/092986712800672076

    Article  CAS  PubMed  Google Scholar 

  41. Chen YS, Wu MJ, Huang CY et al (2011) CD133/Src axis mediates tumor initiating property and epithelial-mesenchymal transition of head and neck cancer. PLoS ONE 6:1–12. https://doi.org/10.1371/journal.pone.0028053

    Article  CAS  Google Scholar 

  42. Sun Y, Kong W, Falk A et al (2009) C0D133 (Prominin) negative human neural stem cells are clonogenic and tripotent. PLoS ONE 4:16–18. https://doi.org/10.1371/journal.pone.0005498

    Article  CAS  Google Scholar 

  43. Barrantes-Freer A, Renovanz M, Eich M et al (2015) CD133 expression is not synonymous to immunoreactivity for AC133 and fluctuates throughout the cell cycle in glioma stem-like cells. PLoS ONE 10:1–16. https://doi.org/10.1371/journal.pone.0130519

    Article  CAS  Google Scholar 

  44. Feng HL, Liu YQ, Yang LJ et al (2010) Expression of CD133 correlates with differentiation of human colon cancer cells. Cancer Biol Ther 9:216–223. https://doi.org/10.4161/cbt.9.3.10664

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by grants from Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank them for their support.

Author information

Authors and Affiliations

  1. Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran

    Marjan Aghajani, Ahad Mokhtarzadeh, Leili Aghebati-Maleki, Sahar Safaei, Zahra Asadzadeh, Khalil Hajiasgharzadeh, Vahid Khaze Shahgoli & Behzad Baradaran

  2. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Behzad Mansoori & Ali Mohammadi

  3. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

Authors
  1. Marjan Aghajani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahad Mokhtarzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leili Aghebati-Maleki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Behzad Mansoori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ali Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sahar Safaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zahra Asadzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Khalil Hajiasgharzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vahid Khaze Shahgoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Behzad Baradaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Behzad Baradaran.

Ethics declarations

Conflict of interests

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aghajani, M., Mokhtarzadeh, A., Aghebati-Maleki, L. et al. CD133 suppression increases the sensitivity of prostate cancer cells to paclitaxel. Mol Biol Rep 47, 3691–3703 (2020). https://doi.org/10.1007/s11033-020-05411-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05411-9

Keywords

Search

Navigation