Abstract
Aim:
To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.
Methods:
A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.
Results:
A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.
Conclusion:
Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.
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References
Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN . The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rev 1993; 19: 351–86.
Hagisawa S, Mikami T, Sato Y . Docetaxel-induced apoptosis in the mitotic phase: electron microscopic and cytochemical studies of human leukemia cells. Med Electron Microsc 1999; 32: 167–74.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12.
Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–97.
He L, Hannon GJ . MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522–31.
Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–66.
Esquela-Kerscher A, Slack FJ . Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–69.
Song B, Wang Y, Xi Y, Kudo K, Bruheim S, Botchkina GI, et al. Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene 2009; 28: 4065–74.
Fujita Y, Kojima K, Hamada N, Ohhashi R, Akao Y, Nozawa Y, et al. Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun 2008; 377: 114–9.
Chen R, Alvero AB, Silasi DA, Kelly MG, Fest S, Visintin I, et al. Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells. Oncogene 2008; 27: 4712–23.
Lo Nigro C, Maffi M, Fischel JL, Formento P, Milano G, Merlano M . The combination of docetaxel and the somatostatin analogue lanreotide on androgen-independent docetaxel-resistant prostate cancer: experimental data. BJU Int 2008; 102: 622–7.
Chan JA, Krichevsky AM, Kosik KS . MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33.
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005; 65: 7065–70.
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133: 647–58.
Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, et al. miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 2009; 69: 7165–9.
Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 2008; 27: 2128–36.
Shiota M, Izumi H, Tanimoto A, Takahashi M, Miyamoto N, Kashiwagi E, et al. Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth. Cancer Res 2009; 69: 3148–56.
Selcuklu SD, Donoghue MT, Spillane C . miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans 2009; 37: 918–25.
Zhu S, Si ML, Wu H, Mo YY . MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 2007; 282: 14328–36.
Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, et al. MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell 2008; 19: 3272–82.
Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, et al. Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol 2006; 177: 8095–102.
Jansen AP, Camalier CE, Colburn NH . Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res 2005; 65: 6034–41.
Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC, et al. Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Mol Cell Biol 2006; 26: 1297–306.
Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, et al. A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Oncogene 2001; 20: 669–76.
Chen Y, Knösel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, et al. Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol 2003; 200: 640–6.
Afonja O, Juste D, Das S, Matsuhashi S, Samuels HH . Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. Oncogene 2004; 23: 8135–45.
Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, et al. Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene 2006; 25: 6101–12.
Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, et al. Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci USA 1999; 96: 14037–42.
Yang HS, Knies JL, Stark C, Colburn NH . Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene 2003; 22: 3712–20.
Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N, Colburn NH . A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol 2004; 24: 3894–906.
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Supplementary information, Figure S1
Relative expression of P-gp and MRP1 in PC3wt and PC3R cells. (DOC 50 kb)
Supplementary information, Figure S2
The Caspase 3/7 activities in PC3R cells when silencing of miR-21 or ectopic expression of PDCD4. (DOC 33 kb)
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Shi, Gh., Ye, Dw., Yao, Xd. et al. Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells. Acta Pharmacol Sin 31, 867–873 (2010). https://doi.org/10.1038/aps.2010.48
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DOI: https://doi.org/10.1038/aps.2010.48
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