Skip to main content

Advertisement

SpringerLink
Log in

MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Curcumin, a natural phytochemical, exhibits potent anticancer activities. Here, we sought to determine the molecular mechanisms underlying the cytotoxic effects of curcumin against human non-small cell lung cancer (NSCLC) cells.

Methods

MTT assay and annexin-V/PI staining were used to analyze the effects of curcumin on the proliferation and apoptosis of A549 cells. The expression of microRNA-21 in curcumin-treated A549 cells was measured by quantitative real-time polymerase chain reaction assay. The protein level of phosphatase and tensin homolog (PTEN), a putative target of microRNA-21, was determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA was performed to modulate the expression of microRNA-21 and PTEN under the treatment of curcumin.

Results

Curcumin at 20–40 μM inhibited cell proliferation and induced apoptosis in A549 cells. Curcumin treatment produced a dose-dependent and significant (P < 0.05) suppression of microRNA-21 expression, compared to untreated A549 cells. Moreover, the protein level of PTEN, a putative target of microRNA-21, was significantly elevated in curcumin-treated A549 cells, as determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA significantly (P < 0.05) reversed the growth suppression and apoptosis induction by curcumin, compared to corresponding controls.

Conclusions

Our data suggest a novel molecular mechanism in which inhibition of microRNA-21 and upregulation of PTEN mediate the anticancer activities of curcumin in NSCLC cells. Suppression of microRNA-21 may thus have therapeutic benefits against this malignancy.

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

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Sechler M, Cizmic AD, Avasarala S, Van Scoyk M, Brzezinski C, Kelley N, et al. Non-small-cell lung cancer: molecular targeted therapy and personalized medicine-drug resistance, mechanisms, and strategies. Pharmgenomics Pers Med. 2013;6:25–36.

    PubMed Central  PubMed  Google Scholar 

  3. Stinchcombe TE, Socinski MA. Current treatments for advanced stage non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:233–41.

    Article  CAS  PubMed  Google Scholar 

  4. Wang T, Nelson RA, Bogardus A, Grannis FW Jr. Five-year lung cancer survival: which advanced stage non-small cell lung cancer patients attain long-term survival? Cancer. 2010;116:1518–25.

    Article  PubMed  Google Scholar 

  5. Park W, Amin AR, Chen ZG, Shin DM. New perspectives of curcumin in cancer prevention. Cancer Prev Res (Phila). 2013;6:387–400.

    Article  CAS  Google Scholar 

  6. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15:195–218.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Ono M, Higuchi T, Takeshima M, Chen C, Nakano S. Antiproliferative and apoptosis-inducing activity of curcumin against human gallbladder adenocarcinoma cells. Anticancer Res. 2013;33:1861–6.

    CAS  PubMed  Google Scholar 

  8. Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P, Goel A. Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-κB and Src protein kinase signaling pathways. PLoS One. 2013;8:e57218.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Killian PH, Kronski E, Michalik KM, Barbieri O, Astigiano S, Sommerhoff CP, et al. Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2. Carcinogenesis. 2012;33:2507–19.

    Article  CAS  PubMed  Google Scholar 

  10. Yang CL, Liu YY, Ma YG, Xue YX, Liu DG, Ren Y, et al. Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through Janus kinase-STAT3 signalling pathway. PLoS One. 2012;7:e37960.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Datta R, Halder SK, Zhang B. Role of TGF-β signaling in curcumin-mediated inhibition of tumorigenicity of human lung cancer cells. J Cancer Res Clin Oncol. 2013;139:563–72.

    Article  CAS  PubMed  Google Scholar 

  12. Markou A, Tsaroucha EG, Kaklamanis L, Fotinou M, Georgoulias V, Lianidou ES. Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem. 2008;54:1696–704.

    Article  CAS  PubMed  Google Scholar 

  13. Liu ZL, Wang H, Liu J, Wang ZX. MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem. 2013;372:35–45.

    Article  CAS  PubMed  Google Scholar 

  14. Mudduluru G, George-William JN, Muppala S, Asangani IA, Kumarswamy R, Nelson LD, et al. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep. 2011;31:185–97.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang J, Du Y, Wu C, Ren X, Ti X, Shi J, et al. Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186* signaling pathway. Oncol Rep. 2010;24:1217–23.

    CAS  PubMed  Google Scholar 

  16. Gao W, Lu X, Liu L, Xu J, Feng D, Shu Y. MiRNA-21: a biomarker predictive for platinum-based adjuvant chemotherapy response in patients with non-small cell lung cancer. Cancer Biol Ther. 2012;13:330–40.

    Article  CAS  PubMed  Google Scholar 

  17. Lin SS, Huang HP, Yang JS, Wu JY, Hsia TC, Lin CC, et al. DNA damage and endoplasmic reticulum stress mediated curcumin-induced cell cycle arrest and apoptosis in human lung carcinoma A-549 cells through the activation caspase cascade- and mitochondrial-dependent pathway. Cancer Lett. 2008;272:77–90.

    Article  CAS  PubMed  Google Scholar 

  18. Qin X, Yan L, Zhao X, Li C, Fu Y. microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer. Oncol Lett. 2012;4:1290–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  20. Nilsen TW. Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet. 2007;23:243–9.

    Article  CAS  PubMed  Google Scholar 

  21. Erson AE, Petty EM. miRNAs and cancer: new research developments and potential clinical applications. Cancer Biol Ther. 2009;8:2317–22.

    Article  CAS  PubMed  Google Scholar 

  22. Gandhy SU, Kim K, Larsen L, Rosengren RJ, Safe S. Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer. 2012;12:564.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Anastasov N, Höfig I, Vasconcellos IG, Rappl K, Braselmann H, Ludyga N, et al. Radiation resistance due to high expression of miR-21 and G2/M checkpoint arrest in breast cancer cells. Radiat Oncol. 2012;7:206.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Zaman MS, Shahryari V, Deng G, Thamminana S, Saini S, Majid S, et al. Up-regulation of microRNA-21 correlates with lower kidney cancer survival. PLoS One. 2012;7:e31060.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res. 2010;70:3606–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–73.

    Article  CAS  PubMed  Google Scholar 

  27. Yu Y, Kanwar SS, Patel BB, Oh PS, Nautiyal J, Sarkar FH, et al. MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFβR2) in colon cancer cells. Carcinogenesis. 2012;33:68–76.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Yamanaka S, Olaru AV, An F, Luvsanjav D, Jin Z, Agarwal R, et al. MicroRNA-21 inhibits Serpini1, a gene with novel tumour suppressive effects in gastric cancer. Dig Liver Dis. 2012;44:589–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Jin C, Zhao Y, Yu L, Xu S, Fu G. MicroRNA-21 mediates the rapamycin-induced suppression of endothelial proliferation and migration. FEBS Lett. 2013;587:378–85.

    Article  CAS  PubMed  Google Scholar 

  30. Zhong Z, Dong Z, Yang L, Gong Z. miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer. J Cancer Res Clin Oncol. 2012;138:1781–8.

    Article  CAS  PubMed  Google Scholar 

  31. Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 2006;51:181–91.

    Article  PubMed  Google Scholar 

  32. Li D, Zhang Y, Xie Y, Xiang J, Zhu Y, Yang J. Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer. Cancer Gene Ther. 2013;20:251–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Respiratory Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China

    W. Zhang & W. Bai

  2. Department of Cardiothoracic Surgery, The First Affiliated Hospital of General Hospital of the Chinese People’s Liberation Army, Fucheng Road 51, Beijing, 100048, People’s Republic of China

    W. Zhang

Authors
  1. W. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, W., Bai, W. & Zhang, W. MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin Transl Oncol 16, 708–713 (2014). https://doi.org/10.1007/s12094-013-1135-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-013-1135-9

Keywords

Search

Navigation