Skip to main content
Top
Published in: World Journal of Surgical Oncology 1/2012

Open Access 01-12-2012 | Research

3p21.3 tumor suppressor gene RBM5 inhibits growth of human prostate cancer PC-3 cells through apoptosis

Authors: Lijing Zhao, Ranwei Li, Chen Shao, Ping Li, Jian Liu, Ke Wang

Published in: World Journal of Surgical Oncology | Issue 1/2012

Login to get access

Abstract

Background

Recent studies have indicated that the nuclear RNA-binding protein RBM5 has the ability to modulate apoptosis and suppress tumor growth. The aim of this study is to investigate the expression of RBM5 in human prostate cancer and its mechanism of tumor suppression.

Methods

The expression of RBM5 protein in cancerous prostatic tissues and normal tissues was examined by IHC. PC-3 cell line was used to determine the apoptotic function of RBM5 in vitro. PC-3 cells were transiently transfected with pcDNA3.1-RBM5. Cell viability was determined by MTT assay. Rhodamine 123 staining and Annexin V analysis were performed to observe the apoptotic activity of PC-3 cells overexpressing RBM5. Expression of apoptosis-related genes was assessed by western blot.

Results

The expression of RBM5 protein was significantly decreased in cancerous prostatic tissues compared to the normal tissues. PC-3 cells overexpressing RBM5 showed not only significant growth inhibition compared with the vector controls, but also dysfunction of mitochondrial membrane potential and increased apoptotic activity. To further define RBM5 function in apoptotic pathways, we investigated differential expression profiles of various BH3-only proteins including Bid, Bad, and Bim, and apoptosis regulatory proteins include P53, cleaved caspase9, and cleaved caspase3. We found that the expression of both BH3-only proteins and apoptosis regulatory proteins was increased in RBM5 transfected cells.

Conclusion

The expression of RBM5 protein was significantly decreased in cancerous prostatic tissues, which suggests that RBM5 plays an important role in the pathogenesis of prostate cancer. RBM5 may induce the apoptosis of prostate cancer PC-3 cells by modulating the mitochondrial apoptotic pathway, and thus RBM5 might be a promising target for gene therapy on prostate cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F: International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012, 61: 1079-1092. 10.1016/j.eururo.2012.02.054.CrossRefPubMed Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F: International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012, 61: 1079-1092. 10.1016/j.eururo.2012.02.054.CrossRefPubMed
2.
go back to reference Zhang L, Wu S, Guo LR, Zhao XJ: Diagnostic strategies and the incidence of prostate cancer: reasons for the low reported incidence of prostate cancer in China. Asian J Androl. 2009, 11: 9-13. 10.1038/aja.2008.21.PubMedCentralCrossRefPubMed Zhang L, Wu S, Guo LR, Zhao XJ: Diagnostic strategies and the incidence of prostate cancer: reasons for the low reported incidence of prostate cancer in China. Asian J Androl. 2009, 11: 9-13. 10.1038/aja.2008.21.PubMedCentralCrossRefPubMed
3.
go back to reference Klein EA, Kupelian PA: Localized prostate cancer: radiation or surgery?. Urol Clin North Am. 2003, 30: 315-330. 10.1016/S0094-0143(02)00179-9. ixCrossRefPubMed Klein EA, Kupelian PA: Localized prostate cancer: radiation or surgery?. Urol Clin North Am. 2003, 30: 315-330. 10.1016/S0094-0143(02)00179-9. ixCrossRefPubMed
4.
go back to reference Kok K, Naylor SL, Buys CH: Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997, 71: 27-92.CrossRefPubMed Kok K, Naylor SL, Buys CH: Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997, 71: 27-92.CrossRefPubMed
5.
go back to reference Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, Fondon JW, Garner HR, McKay B, Latif F, Lerman MI, Lam S, Gazdar AF, Minna JD: High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 2000, 60: 1949-1960.PubMed Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, Fondon JW, Garner HR, McKay B, Latif F, Lerman MI, Lam S, Gazdar AF, Minna JD: High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 2000, 60: 1949-1960.PubMed
6.
go back to reference Ji L, Minna JD, Roth JA: 3p21.3 tumor suppressor cluster: prospects for translational applications. Future Oncol. 2005, 1: 79-92. 10.1517/14796694.1.1.79.CrossRefPubMed Ji L, Minna JD, Roth JA: 3p21.3 tumor suppressor cluster: prospects for translational applications. Future Oncol. 2005, 1: 79-92. 10.1517/14796694.1.1.79.CrossRefPubMed
7.
go back to reference Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT: Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5. Genes Cells. 2003, 8: 109-119. 10.1046/j.1365-2443.2003.00619.x.CrossRefPubMed Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT: Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5. Genes Cells. 2003, 8: 109-119. 10.1046/j.1365-2443.2003.00619.x.CrossRefPubMed
8.
go back to reference Edamatsu H, Kaziro Y, Itoh H: LUCA15, a putative tumour suppressor gene encoding an RNA-binding nuclear protein, is down-regulated in ras-transformed Rat-1 cells. Genes Cells. 2000, 5: 849-858. 10.1046/j.1365-2443.2000.00370.x.CrossRefPubMed Edamatsu H, Kaziro Y, Itoh H: LUCA15, a putative tumour suppressor gene encoding an RNA-binding nuclear protein, is down-regulated in ras-transformed Rat-1 cells. Genes Cells. 2000, 5: 849-858. 10.1046/j.1365-2443.2000.00370.x.CrossRefPubMed
9.
go back to reference Welling DB, Lasak JM, Akhmametyeva E, Ghaheri B, Chang LS: cDNA microarray analysis of vestibular schwannomas. Otol Neurotol. 2002, 23: 736-748. 10.1097/00129492-200209000-00022.CrossRefPubMed Welling DB, Lasak JM, Akhmametyeva E, Ghaheri B, Chang LS: cDNA microarray analysis of vestibular schwannomas. Otol Neurotol. 2002, 23: 736-748. 10.1097/00129492-200209000-00022.CrossRefPubMed
10.
go back to reference Oh JJ, West AR, Fishbein MC, Slamon DJ: A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3. Cancer Res. 2002, 62: 3207-3213.PubMed Oh JJ, West AR, Fishbein MC, Slamon DJ: A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3. Cancer Res. 2002, 62: 3207-3213.PubMed
11.
go back to reference Liang H, Zhang J, Shao C, Zhao L, Xu W, Sutherland LC, Wang K: Differential expression of RBM5. EGFR and KRAS mRNA and protein in non-small cell lung cancer tissues. J Exp Clin Cancer Res. 2012, 31: 36-10.1186/1756-9966-31-36.PubMedCentralCrossRefPubMed Liang H, Zhang J, Shao C, Zhao L, Xu W, Sutherland LC, Wang K: Differential expression of RBM5. EGFR and KRAS mRNA and protein in non-small cell lung cancer tissues. J Exp Clin Cancer Res. 2012, 31: 36-10.1186/1756-9966-31-36.PubMedCentralCrossRefPubMed
12.
go back to reference Sutherland LC, Wang K, Robinson AG: RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol. 2010, 5: 294-298. 10.1097/JTO.0b013e3181c6e330.CrossRefPubMed Sutherland LC, Wang K, Robinson AG: RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol. 2010, 5: 294-298. 10.1097/JTO.0b013e3181c6e330.CrossRefPubMed
13.
go back to reference Maarabouni MM, Williams GT: The antiapoptotic RBM5/LUCA-15/H37 gene and its role in apoptosis and human cancer: research update. ScientificWorldJournal. 2006, 6: 1705-1712.CrossRefPubMed Maarabouni MM, Williams GT: The antiapoptotic RBM5/LUCA-15/H37 gene and its role in apoptosis and human cancer: research update. ScientificWorldJournal. 2006, 6: 1705-1712.CrossRefPubMed
14.
go back to reference Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ: 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res. 2006, 66: 3419-3427. 10.1158/0008-5472.CAN-05-1667.CrossRefPubMed Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ: 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res. 2006, 66: 3419-3427. 10.1158/0008-5472.CAN-05-1667.CrossRefPubMed
15.
go back to reference Li P, Wang K, Zhang J, Zhao L, Liang H, Shao C, Sutherland LC: The 3p21.3 tumor suppressor RBM5 resensitizes cisplatin-resistant human non-small cell lung cancer cells to cisplatin. Cancer Epidemiol. 2012, 36: 481-489. 10.1016/j.canep.2012.04.004.CrossRefPubMed Li P, Wang K, Zhang J, Zhao L, Liang H, Shao C, Sutherland LC: The 3p21.3 tumor suppressor RBM5 resensitizes cisplatin-resistant human non-small cell lung cancer cells to cisplatin. Cancer Epidemiol. 2012, 36: 481-489. 10.1016/j.canep.2012.04.004.CrossRefPubMed
16.
go back to reference Rintala-Maki ND, Abrasonis V, Burd M, Sutherland LC: Genetic instability of RBM5/LUCA-15/H37 in MCF-7 breast carcinoma sublines may affect susceptibility to apoptosis. Cell Biochem Funct. 2004, 22: 307-313. 10.1002/cbf.1106.CrossRefPubMed Rintala-Maki ND, Abrasonis V, Burd M, Sutherland LC: Genetic instability of RBM5/LUCA-15/H37 in MCF-7 breast carcinoma sublines may affect susceptibility to apoptosis. Cell Biochem Funct. 2004, 22: 307-313. 10.1002/cbf.1106.CrossRefPubMed
17.
go back to reference Senchenko VN, Liu J, Loginov W, Bazov I, Angeloni D, Seryogin Y, Ermilova V, Kazubskaya T, Garkavtseva R, Zabarovska VI, Kashuba VI, Kisselev LL, Minna JD, Lerman MI, Klein G, Braga EA, Zabarovsky ER: Discovery of frequent homozygous deletions in chromosome 3p21.3 LUCA and AP20 regions in renal, lung and breast carcinomas. Oncogene. 2004, 23: 5719-5728. 10.1038/sj.onc.1207760.CrossRefPubMed Senchenko VN, Liu J, Loginov W, Bazov I, Angeloni D, Seryogin Y, Ermilova V, Kazubskaya T, Garkavtseva R, Zabarovska VI, Kashuba VI, Kisselev LL, Minna JD, Lerman MI, Klein G, Braga EA, Zabarovsky ER: Discovery of frequent homozygous deletions in chromosome 3p21.3 LUCA and AP20 regions in renal, lung and breast carcinomas. Oncogene. 2004, 23: 5719-5728. 10.1038/sj.onc.1207760.CrossRefPubMed
18.
go back to reference Rintala-Maki ND, Sutherland LC: LUCA-15/RBM5, a putative tumour suppressor, enhances multiple receptor-initiated death signals. Apoptosis. 2004, 9: 475-484.CrossRefPubMed Rintala-Maki ND, Sutherland LC: LUCA-15/RBM5, a putative tumour suppressor, enhances multiple receptor-initiated death signals. Apoptosis. 2004, 9: 475-484.CrossRefPubMed
19.
go back to reference Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT: LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Oncogene. 2000, 19: 3774-3781. 10.1038/sj.onc.1203720.CrossRefPubMed Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT: LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Oncogene. 2000, 19: 3774-3781. 10.1038/sj.onc.1203720.CrossRefPubMed
20.
go back to reference Johnstone RW, Ruefli AA, Lowe SW: Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002, 108: 153-164. 10.1016/S0092-8674(02)00625-6.CrossRefPubMed Johnstone RW, Ruefli AA, Lowe SW: Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002, 108: 153-164. 10.1016/S0092-8674(02)00625-6.CrossRefPubMed
21.
go back to reference Hsu JL, Ho YF, Li TK, Chen CS, Hsu LC, Guh JH: Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCdelta-independent pathway. Biochem Pharmacol. 2012, 84: 59-67. 10.1016/j.bcp.2012.03.023.PubMedCentralCrossRefPubMed Hsu JL, Ho YF, Li TK, Chen CS, Hsu LC, Guh JH: Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCdelta-independent pathway. Biochem Pharmacol. 2012, 84: 59-67. 10.1016/j.bcp.2012.03.023.PubMedCentralCrossRefPubMed
22.
go back to reference Ramaswamy S, Ross KN, Lander ES, Golub TR: A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003, 33: 49-54. 10.1038/ng1060.CrossRefPubMed Ramaswamy S, Ross KN, Lander ES, Golub TR: A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003, 33: 49-54. 10.1038/ng1060.CrossRefPubMed
23.
go back to reference Kotlajich MV, Hertel KJ: Death by splicing: tumor suppressor RBM5 freezes splice-site pairing. Mol Cell. 2008, 32: 162-164. 10.1016/j.molcel.2008.10.008.CrossRefPubMed Kotlajich MV, Hertel KJ: Death by splicing: tumor suppressor RBM5 freezes splice-site pairing. Mol Cell. 2008, 32: 162-164. 10.1016/j.molcel.2008.10.008.CrossRefPubMed
24.
go back to reference Farina B, Fattorusso R, Pellecchia M: Targeting zinc finger domains with small molecules: solution structure and binding studies of the RanBP2-type zinc finger of RBM5. Chembiochem. 2011, 12: 2837-2845. 10.1002/cbic.201100582.PubMedCentralCrossRefPubMed Farina B, Fattorusso R, Pellecchia M: Targeting zinc finger domains with small molecules: solution structure and binding studies of the RanBP2-type zinc finger of RBM5. Chembiochem. 2011, 12: 2837-2845. 10.1002/cbic.201100582.PubMedCentralCrossRefPubMed
25.
go back to reference Sutherland LC, Lerman M, Williams GT, Miller BA: LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. Oncogene. 2001, 20: 2713-2719. 10.1038/sj.onc.1204371.CrossRefPubMed Sutherland LC, Lerman M, Williams GT, Miller BA: LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. Oncogene. 2001, 20: 2713-2719. 10.1038/sj.onc.1204371.CrossRefPubMed
26.
go back to reference Oh JJ, Taschereau EO, Koegel AK, Ginther CL, Rotow JK, Isfahani KZ, Slamon DJ: RBM5/H37 tumor suppressor, located at the lung cancer hot spot 3p21.3, alters expression of genes involved in metastasis. Lung Cancer. 2010, 70: 253-262. 10.1016/j.lungcan.2010.02.012.CrossRefPubMed Oh JJ, Taschereau EO, Koegel AK, Ginther CL, Rotow JK, Isfahani KZ, Slamon DJ: RBM5/H37 tumor suppressor, located at the lung cancer hot spot 3p21.3, alters expression of genes involved in metastasis. Lung Cancer. 2010, 70: 253-262. 10.1016/j.lungcan.2010.02.012.CrossRefPubMed
27.
go back to reference Kobayashi T, Ishida J, Musashi M, Ota S, Yoshida T, Shimizu Y, Chuma M, Kawakami H, Asaka M, Tanaka J, Imamura M, Kobayashi M, Itoh H, Edamatsu H, Sutherland LC, Brachmann RK: p53 transactivation is involved in the antiproliferative activity of the putative tumor suppressor RBM5. Int J Cancer. 2011, 128: 304-318. 10.1002/ijc.25345.CrossRefPubMed Kobayashi T, Ishida J, Musashi M, Ota S, Yoshida T, Shimizu Y, Chuma M, Kawakami H, Asaka M, Tanaka J, Imamura M, Kobayashi M, Itoh H, Edamatsu H, Sutherland LC, Brachmann RK: p53 transactivation is involved in the antiproliferative activity of the putative tumor suppressor RBM5. Int J Cancer. 2011, 128: 304-318. 10.1002/ijc.25345.CrossRefPubMed
28.
go back to reference Walensky LD, Gavathiotis E: BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem Sci. 2011, 36: 642-652. 10.1016/j.tibs.2011.08.009.PubMedCentralCrossRefPubMed Walensky LD, Gavathiotis E: BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem Sci. 2011, 36: 642-652. 10.1016/j.tibs.2011.08.009.PubMedCentralCrossRefPubMed
29.
go back to reference Cory S, Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002, 2: 647-656. 10.1038/nrc883.CrossRefPubMed Cory S, Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002, 2: 647-656. 10.1038/nrc883.CrossRefPubMed
30.
31.
go back to reference Li JY, Furuichi Y, Matsuoka N, Mutoh S, Yanagihara T: Tacrolimus (FK506) attenuates biphasic cytochrome c release and Bad phosphorylation following transient cerebral ischemia in mice. Neuroscience. 2006, 142: 789-797. 10.1016/j.neuroscience.2006.06.064.CrossRefPubMed Li JY, Furuichi Y, Matsuoka N, Mutoh S, Yanagihara T: Tacrolimus (FK506) attenuates biphasic cytochrome c release and Bad phosphorylation following transient cerebral ischemia in mice. Neuroscience. 2006, 142: 789-797. 10.1016/j.neuroscience.2006.06.064.CrossRefPubMed
32.
go back to reference Premkumar DR, Jane EP, DiDomenico JD, Vukmer NA, Agostino NR, Pollack IF: ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines. J Pharmacol Exp Ther. 2012, 341: 859-872. 10.1124/jpet.112.191536.PubMedCentralCrossRefPubMed Premkumar DR, Jane EP, DiDomenico JD, Vukmer NA, Agostino NR, Pollack IF: ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines. J Pharmacol Exp Ther. 2012, 341: 859-872. 10.1124/jpet.112.191536.PubMedCentralCrossRefPubMed
33.
go back to reference Garrison SP, Phillips DC, Jeffers JR, Chipuk JE, Parsons MJ, Rehg JE, Opferman JT, Green DR, Zambetti GP: Genetically defining the mechanism of Puma- and Bim-induced apoptosis. Cell Death Differ. 2012, 19: 642-649. 10.1038/cdd.2011.136.PubMedCentralCrossRefPubMed Garrison SP, Phillips DC, Jeffers JR, Chipuk JE, Parsons MJ, Rehg JE, Opferman JT, Green DR, Zambetti GP: Genetically defining the mechanism of Puma- and Bim-induced apoptosis. Cell Death Differ. 2012, 19: 642-649. 10.1038/cdd.2011.136.PubMedCentralCrossRefPubMed
Metadata
Title
3p21.3 tumor suppressor gene RBM5 inhibits growth of human prostate cancer PC-3 cells through apoptosis
Authors
Lijing Zhao
Ranwei Li
Chen Shao
Ping Li
Jian Liu
Ke Wang
Publication date
01-12-2012
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2012
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/1477-7819-10-247

Other articles of this Issue 1/2012

World Journal of Surgical Oncology 1/2012 Go to the issue