BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Identification of simvastatin-regulated targets associated with JNK activation in DU145 human prostate cancer cell death signaling

  • Jung, Eun Joo (Department of Biochemistry, Gyeongsang National University School of Medicine) ;
  • Chung, Ky Hyun (Department of Urology, Gyeongsang National University Hospital) ;
  • Kim, Choong Won (Department of Biochemistry, Gyeongsang National University School of Medicine)
  • Received : 2017.05.26
  • Accepted : 2017.08.03
  • Published : 2017.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

The results of this study show that c-Jun N-terminal kinase (JNK) activation was associated with the enhancement of docetaxel-induced cytotoxicity by simvastatin in DU145 human prostate cancer cells. To better understand the basic molecular mechanisms, we investigated simvastatin-regulated targets during simvastatin-induced cell death in DU145 cells using two-dimensional (2D) proteomic analysis. Thus, vimentin, Ras-related protein Rab-1B (RAB1B), cytoplasmic hydroxymethylglutaryl-CoA synthase (cHMGCS), thioredoxin domain-containing protein 5 (TXNDC5), heterogeneous nuclear ribonucleoprotein K (hnRNP K), N-myc downstream-regulated gene 1 (NDRG1), and isopentenyl-diphosphate Delta-isomerase 1 (IDI1) protein spots were identified as simvastatin-regulated targets involved in DU145 cell death signaling pathways. Moreover, the JNK inhibitor SP600125 significantly inhibited the upregulation of NDRG1 and IDI protein levels by combination treatment of docetaxel and simvastatin. These results suggest that NDRG1 and IDI could at least play an important role in DU145 cell death signaling as simvastatinregulated targets associated with JNK activation.

Keywords

References

  1. Katsogiannou M, Ziouziou H, Karaki S, Andrieu C, Henry de Villeneuve M and Rocchi P (2015) The hallmarks of castration-resistant prostate cancers. Cancer Treat Rev 41, 588-597 https://doi.org/10.1016/j.ctrv.2015.05.003
  2. Krycer JR and Brown AJ (2013) Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective. Biochim Biophys Acta 1835, 219-229
  3. Osmak M (2012) Statins and cancer: Current and future prospects. Cancer Lett 324, 1-12 https://doi.org/10.1016/j.canlet.2012.04.011
  4. Altwairgi AK (2015) Statins are potential anticancerous agents (Review). Oncol Rep 33, 1019-1039 https://doi.org/10.3892/or.2015.3741
  5. Gordon JA, Midha A, Szeitz A et al (2016) Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. Prostate Cancer Prostatic Dis 19, 21-27 https://doi.org/10.1038/pcan.2015.37
  6. Yu O, Eberg M, Benayoun S et al (2014) Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 32, 5-11
  7. Bogoyevitch MA and Arthur PG (2008) Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim Biophys Acta 1784, 76-93 https://doi.org/10.1016/j.bbapap.2007.09.013
  8. Koyuturk M, Ersoz M and Altiok N (2004) Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Neurosci Lett 370, 212-217 https://doi.org/10.1016/j.neulet.2004.08.020
  9. Chen YJ and Chang LS (2014) Simvastatin induces $NF{\kappa}B$/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells. Biochem Pharmacol 92, 530-543 https://doi.org/10.1016/j.bcp.2014.09.026
  10. Koyuturk M, Ersoz M and Altiok N (2007) Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK. Cancer Lett 250, 220-228 https://doi.org/10.1016/j.canlet.2006.10.009
  11. Gopalan A, Yu W, Sanders BG and Kline K (2013) Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway. Cancer Lett 329, 9-16 https://doi.org/10.1016/j.canlet.2012.08.031
  12. Zhang S, Doudican NA, Quay E and Orlow SJ (2011) Fluvastatin enhances sorafenib cytotoxicity in melanoma cells via modulation of AKT and JNK signaling pathways. Anticancer Res 31, 3259-3265
  13. Goc A, Kochuparambil ST, Al-Husein B, Al-Azayzih A, Mohammad S and Somanath PR (2012) Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis. BMC Cancer 12, e409 https://doi.org/10.1186/1471-2407-12-409
  14. Chen X, Liu Y, Wu J et al (2016) Mechanistic study of inhibitory effects of atorvastatin and docetaxel in combination on prostate cancer. Cancer Genomics Proteomics 13, 151-160
  15. Pienaar IS, Schallert T, Hattingh S and Daniels WM (2009) Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin: implications for models of neural degeneration. J Neural Transm 116, 791-806 https://doi.org/10.1007/s00702-009-0247-4
  16. Campos-Martorell M, Salvador N, Monge M et al (2014) Brain proteomics identifies potential simvastatin targets in acute phase of stroke in a rat embolic model. J Neurochem 130, 301-312 https://doi.org/10.1111/jnc.12719
  17. Ponce J, Brea D, Carrascal M et al (2010) The effect of simvastatin on the proteome of detergent-resistant membrane domains: Decreases of specific proteins previously related to cytoskeleton regulation, calcium homeostasis and cell fate. Proteomics 10, 1954-1965 https://doi.org/10.1002/pmic.200900055
  18. Hwang R, Lee EJ, Kim MH et al (2004) Calcyclin, a $Ca^{2+}$ ion-binding protein, contributes to the anabolic effects of simvastatin on bone. J Biol Chem 279, 21239-21247 https://doi.org/10.1074/jbc.M312771200
  19. Cho YE, Moon PG, Lee JE et al (2013) Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin-induced hepatotoxicity. Proteomics 13, 1257-1275 https://doi.org/10.1002/pmic.201200368
  20. Hirai T and Chida K (2003) Protein kinase $C{\zeta}$ ($PKC{\zeta}$): activation mechanisms and cellular functions. J Biochem 133, 1-7 https://doi.org/10.1093/jb/mvg017
  21. Huang WC and Hung MC (2013) Beyond NF-${\kappa}B$ activation: nuclear functions of $I{\kappa}B$ kinase ${\alpha}$. J Biomed Sci 20, e3 https://doi.org/10.1186/1423-0127-20-3
  22. Liu JJ and Zhang J (2013) Sequencing systemic therapies in metastatic castration-resistant prostate cancer. Cancer Control 20, 181-187 https://doi.org/10.1177/107327481302000306
  23. Xie F, Liu J, Li C and Zhao Y (2016) Simvastatin blocks TGF-${\beta}1$-induced epithelial-mesenchymal transition in human prostate cancer cells. Oncol Lett 11, 3377-3383 https://doi.org/10.3892/ol.2016.4404
  24. Jiang HL, Sun HF, Gao SP et al (2015) Loss of RAB1B promotes triple-negative breast cancer metastasis by activating TGF-${\beta}$/SMAD signaling. Oncotarget 6, 16352-16365 https://doi.org/10.18632/oncotarget.3877
  25. Vincent EE, Elder DJ, Phillips L et al (2011) Overexpression of the TXNDC5 protein in non-small cell lung carcinoma. Anticancer Res 31, 1577-1582
  26. Wang L, Song G, Chang X et al (2015) The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. Oncogene 34, 4735-4745 https://doi.org/10.1038/onc.2014.401
  27. Dixon KM, Lui GY, Kovacevic Z et al (2013) Dp44mT targets the AKT, TGF-${\beta}$ and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells. Br J Cancer 108, 409-419 https://doi.org/10.1038/bjc.2012.582
  28. Barboro P, Salvi S, Rubagotti A et al (2014) Prostate cancer: Prognostic significance of the association of heterogeneous nuclear ribonucleoprotein K and androgen receptor expression. Int J Oncol 44, 1589-1598 https://doi.org/10.3892/ijo.2014.2345
  29. Barboro P, Borzi L, Repaci E, Ferrari N and Balbi C (2013) Androgen receptor activity is affected by both nuclear matrix localization and the phosphorylation status of the heterogeneous nuclear ribonucleoprotein K in antiandrogen-treated LNCaP cells. PLoS One 8, e79212 https://doi.org/10.1371/journal.pone.0079212
  30. Clendening JW, Pandyra A, Boutros PC et al (2010) Dysregulation of the mevalonate pathway promotes transformation. Proc Natl Acad Sci U S A 107, 15051-15056 https://doi.org/10.1073/pnas.0910258107
  31. Berthelot K, Estevez Y, Deffieux A and Peruch F (2012) Isopentenyl diphosphate isomerase: A checkpoint to isoprenoid biosynthesis. Biochimie 94, 1621-1634 https://doi.org/10.1016/j.biochi.2012.03.021
  32. Sharon C, Baranwal S, Patel NJ et al (2015) Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo. Oncotarget 6, 15332-15347 https://doi.org/10.18632/oncotarget.3684

Cited by

  1. Bioactivity evaluations of betulin identified from the bark of Betula platyphylla var. japonica for cancer therapy vol.41, pp.8, 2018, https://doi.org/10.1007/s12272-018-1064-9