Skip to main content
Top
Published in: Tumor Biology 5/2015

01-05-2015 | Research Article

RBPJ inhibition impairs the growth of lung cancer

Authors: Qun Lv, Ronglin Shen, Jianjun Wang

Published in: Tumor Biology | Issue 5/2015

Login to get access

Abstract

The exact effects of the modulation of Notch signaling pathway on cell growth have been shown to depend on tumor cell type. Recombination signal-binding protein Jκ (RBPJ) is a key transcription factor downstream of receptor activation in Notch signaling pathway. Here, we evaluated the effects of RBPJ inhibition on the growth of lung cancer cells. We found that a short hairpin interfering RNA (shRNA) for RBPJ efficiently inhibited RBPJ expression in lung cancer cells, resulting in a significant decrease in the cell growth. Further analyses showed that RBPJ inhibition altered the levels of its downstream targets, including p21, p27, CDK2, Hes1, Bcl-2, and SKP2, to prevent the cells from growing. Our data thus suggest that shRNA intervention of RBPJ expression could be a promising therapeutic approach for treating human lung cancer.
Literature
1.
go back to reference Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5:S389–96.PubMedPubMedCentral Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5:S389–96.PubMedPubMedCentral
2.
go back to reference Mitsudomi T, Suda K, Yatabe Y. Surgery for nsclc in the era of personalized medicine. Nat Rev Clin Oncol. 2013;10:235–44.CrossRefPubMed Mitsudomi T, Suda K, Yatabe Y. Surgery for nsclc in the era of personalized medicine. Nat Rev Clin Oncol. 2013;10:235–44.CrossRefPubMed
3.
go back to reference Pallis AG, Syrigos KN. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer. 2013;80:120–30.CrossRefPubMed Pallis AG, Syrigos KN. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer. 2013;80:120–30.CrossRefPubMed
4.
go back to reference Jian H, Zhao Y, Liu B, Lu S. SEMA4b inhibits MMP9 to prevent metastasis of non-small cell lung cancer. Tumour Biol. 2014;35:11051–6.CrossRefPubMed Jian H, Zhao Y, Liu B, Lu S. SEMA4b inhibits MMP9 to prevent metastasis of non-small cell lung cancer. Tumour Biol. 2014;35:11051–6.CrossRefPubMed
5.
go back to reference Pei J, Lou Y, Zhong R, Han B. MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer. Tumour Biol. 2014;35:6673–8.CrossRefPubMed Pei J, Lou Y, Zhong R, Han B. MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer. Tumour Biol. 2014;35:6673–8.CrossRefPubMed
6.
go back to reference 6 Wang W, Wu X, Tian Y: Crosstalk of AP4 and TGFbeta receptor signaling in NSCLC. Tumour Biol 2014. 6 Wang W, Wu X, Tian Y: Crosstalk of AP4 and TGFbeta receptor signaling in NSCLC. Tumour Biol 2014.
7.
go back to reference Hu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol. 2012;727:186–98.CrossRefPubMed Hu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol. 2012;727:186–98.CrossRefPubMed
8.
go back to reference Wang Z, Li Y, Banerjee S, Sarkar FH. Exploitation of the notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 2008;28:3621–30.PubMed Wang Z, Li Y, Banerjee S, Sarkar FH. Exploitation of the notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 2008;28:3621–30.PubMed
9.
go back to reference Hsieh JJ, Hayward SD. Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. Science. 1995;268:560–3.CrossRefPubMed Hsieh JJ, Hayward SD. Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. Science. 1995;268:560–3.CrossRefPubMed
10.
go back to reference Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. Dynamic binding of RBPJ is determined by notch signaling status. Genes Dev. 2013;27:1059–71.CrossRefPubMedPubMedCentral Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. Dynamic binding of RBPJ is determined by notch signaling status. Genes Dev. 2013;27:1059–71.CrossRefPubMedPubMedCentral
11.
go back to reference Hori K, Cholewa-Waclaw J, Nakada Y, Glasgow SM, Masui T, Henke RM, et al. A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of notch signaling. Genes Dev. 2008;22:166–78.CrossRefPubMedPubMedCentral Hori K, Cholewa-Waclaw J, Nakada Y, Glasgow SM, Masui T, Henke RM, et al. A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of notch signaling. Genes Dev. 2008;22:166–78.CrossRefPubMedPubMedCentral
12.
go back to reference Guo D, Ye J, Dai J, Li L, Chen F, Ma D, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res. 2009;33:678–85.CrossRefPubMed Guo D, Ye J, Dai J, Li L, Chen F, Ma D, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res. 2009;33:678–85.CrossRefPubMed
13.
go back to reference Gao F, Yao M, Shi Y, Hao J, Ren Y, Liu Q, et al. Notch pathway is involved in high glucose-induced apoptosis in podocytes via Bcl-2 and p53 pathways. J Cell Biochem. 2013;114:1029–38.CrossRefPubMed Gao F, Yao M, Shi Y, Hao J, Ren Y, Liu Q, et al. Notch pathway is involved in high glucose-induced apoptosis in podocytes via Bcl-2 and p53 pathways. J Cell Biochem. 2013;114:1029–38.CrossRefPubMed
14.
go back to reference Jarriault S, Le Bail O, Hirsinger E, Pourquie O, Logeat F, Strong CF, et al. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998;18:7423–31.CrossRefPubMedPubMedCentral Jarriault S, Le Bail O, Hirsinger E, Pourquie O, Logeat F, Strong CF, et al. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998;18:7423–31.CrossRefPubMedPubMedCentral
15.
go back to reference Dohda T, Maljukova A, Liu L, Heyman M, Grander D, Brodin D, et al. Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in t-cell acute lymphoblastic leukemia cell lines. Exp Cell Res. 2007;313:3141–52.CrossRefPubMed Dohda T, Maljukova A, Liu L, Heyman M, Grander D, Brodin D, et al. Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in t-cell acute lymphoblastic leukemia cell lines. Exp Cell Res. 2007;313:3141–52.CrossRefPubMed
16.
go back to reference Nakamura T, Miyagawa S, Katsu Y, Mizutani T, Sato T, Takeuchi T, et al. P21 and notch signalings in the persistently altered vagina induced by neonatal diethylstilbestrol exposure in mice. J Vet Med Sci. 2012;74:1589–95.CrossRefPubMed Nakamura T, Miyagawa S, Katsu Y, Mizutani T, Sato T, Takeuchi T, et al. P21 and notch signalings in the persistently altered vagina induced by neonatal diethylstilbestrol exposure in mice. J Vet Med Sci. 2012;74:1589–95.CrossRefPubMed
17.
go back to reference Marcelo KL, Sills TM, Coskun S, Vasavada H, Sanglikar S, Goldie LC, et al. Hemogenic endothelial cell specification requires c-Kit, notch signaling, and p27-mediated cell-cycle control. Dev Cell. 2013;27:504–15.CrossRefPubMedPubMedCentral Marcelo KL, Sills TM, Coskun S, Vasavada H, Sanglikar S, Goldie LC, et al. Hemogenic endothelial cell specification requires c-Kit, notch signaling, and p27-mediated cell-cycle control. Dev Cell. 2013;27:504–15.CrossRefPubMedPubMedCentral
18.
go back to reference Harashima H, Dissmeyer N, Schnittger A. Cell cycle control across the eukaryotic kingdom. Trends Cell Biol. 2013;23:345–56.CrossRefPubMed Harashima H, Dissmeyer N, Schnittger A. Cell cycle control across the eukaryotic kingdom. Trends Cell Biol. 2013;23:345–56.CrossRefPubMed
19.
go back to reference Teixeira LK, Reed SI. Ubiquitin ligases and cell cycle control. Annu Rev Biochem. 2013;82:387–414.CrossRefPubMed Teixeira LK, Reed SI. Ubiquitin ligases and cell cycle control. Annu Rev Biochem. 2013;82:387–414.CrossRefPubMed
20.
go back to reference Maraver A, Fernandez-Marcos PJ, Herranz D, Canamero M, Munoz-Martin M, Gomez-Lopez G, et al. Therapeutic effect of gamma-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK. Cancer Cell. 2012;22:222–34.CrossRefPubMed Maraver A, Fernandez-Marcos PJ, Herranz D, Canamero M, Munoz-Martin M, Gomez-Lopez G, et al. Therapeutic effect of gamma-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK. Cancer Cell. 2012;22:222–34.CrossRefPubMed
21.
go back to reference Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70:4840–9.CrossRefPubMed Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70:4840–9.CrossRefPubMed
22.
go back to reference Hu XB, Feng F, Wang YC, Wang L, He F, Dou GR, et al. Blockade of notch signaling in tumor-bearing mice may lead to tumor regression, progression, or metastasis, depending on tumor cell types. Neoplasia. 2009;11:32–8.CrossRefPubMedPubMedCentral Hu XB, Feng F, Wang YC, Wang L, He F, Dou GR, et al. Blockade of notch signaling in tumor-bearing mice may lead to tumor regression, progression, or metastasis, depending on tumor cell types. Neoplasia. 2009;11:32–8.CrossRefPubMedPubMedCentral
23.
go back to reference Dou GR, Wang YC, Hu XB, Hou LH, Wang CM, Xu JF, et al. RBP-J, the transcription factor downstream of notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J. 2008;22:1606–17.CrossRefPubMed Dou GR, Wang YC, Hu XB, Hou LH, Wang CM, Xu JF, et al. RBP-J, the transcription factor downstream of notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J. 2008;22:1606–17.CrossRefPubMed
24.
go back to reference Nagao H, Setoguchi T, Kitamoto S, Ishidou Y, Nagano S, Yokouchi M, et al. RBPJ is a novel target for rhabdomyosarcoma therapy. PLoS One. 2012;7:e39268.CrossRefPubMedPubMedCentral Nagao H, Setoguchi T, Kitamoto S, Ishidou Y, Nagano S, Yokouchi M, et al. RBPJ is a novel target for rhabdomyosarcoma therapy. PLoS One. 2012;7:e39268.CrossRefPubMedPubMedCentral
25.
go back to reference Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. Rational sirna design for rna interference. Nat Biotechnol. 2004;22:326–30.CrossRefPubMed Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. Rational sirna design for rna interference. Nat Biotechnol. 2004;22:326–30.CrossRefPubMed
26.
go back to reference Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–1220.CrossRefPubMedPubMedCentral Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–1220.CrossRefPubMedPubMedCentral
27.
go back to reference Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP. Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle. 2010;9:689–99.CrossRefPubMed Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP. Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle. 2010;9:689–99.CrossRefPubMed
28.
go back to reference Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat. 2007;10:13–29.CrossRefPubMed Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat. 2007;10:13–29.CrossRefPubMed
29.
go back to reference Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 2003;13:65–70.CrossRefPubMed Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 2003;13:65–70.CrossRefPubMed
30.
31.
go back to reference Theys J, Yahyanejad S, Habets R, Span P, Dubois L, Paesmans K, et al. High notch activity induces radiation resistance in non small cell lung cancer. Radiother Oncol. 2013;108:440–5.CrossRefPubMedPubMedCentral Theys J, Yahyanejad S, Habets R, Span P, Dubois L, Paesmans K, et al. High notch activity induces radiation resistance in non small cell lung cancer. Radiother Oncol. 2013;108:440–5.CrossRefPubMedPubMedCentral
32.
go back to reference Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin Cancer Res. 2013;19:1972–80.CrossRefPubMedPubMedCentral Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin Cancer Res. 2013;19:1972–80.CrossRefPubMedPubMedCentral
34.
go back to reference Xie M, Zhang L, He CS, Xu F, Liu JL, Hu ZH, et al. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J Cell Biochem. 2012;113:1501–13.PubMed Xie M, Zhang L, He CS, Xu F, Liu JL, Hu ZH, et al. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J Cell Biochem. 2012;113:1501–13.PubMed
35.
go back to reference Ji X, Wang Z, Geamanu A, Sarkar FH, Gupta SV. Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by delta-tocotrienol is associated with notch-1 down-regulation. J Cell Biochem. 2011;112:2773–83.CrossRefPubMed Ji X, Wang Z, Geamanu A, Sarkar FH, Gupta SV. Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by delta-tocotrienol is associated with notch-1 down-regulation. J Cell Biochem. 2011;112:2773–83.CrossRefPubMed
37.
go back to reference Garcia Campelo MR, Alonso Curbera G, Aparicio Gallego G, Grande Pulido E, Anton Aparicio LM. Stem cell and lung cancer development: blaming the Wnt, Hh and Notch signalling pathway. Clin Transl Oncol. 2011;13:77–83.CrossRefPubMed Garcia Campelo MR, Alonso Curbera G, Aparicio Gallego G, Grande Pulido E, Anton Aparicio LM. Stem cell and lung cancer development: blaming the Wnt, Hh and Notch signalling pathway. Clin Transl Oncol. 2011;13:77–83.CrossRefPubMed
38.
go back to reference Westhoff B, Colaluca IN, D’Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the notch pathway in lung cancer. Proc Natl Acad Sci U S A. 2009;106:22293–8.CrossRefPubMedPubMedCentral Westhoff B, Colaluca IN, D’Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the notch pathway in lung cancer. Proc Natl Acad Sci U S A. 2009;106:22293–8.CrossRefPubMedPubMedCentral
39.
go back to reference Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61:3200–5.PubMed Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61:3200–5.PubMed
40.
go back to reference Tilesi F, Fradiani P, Socci V, Willems D, Ascenzioni F. Design and validation of siRNAs and shRNAs. Curr Opin Mol Ther. 2009;11:156–64.PubMed Tilesi F, Fradiani P, Socci V, Willems D, Ascenzioni F. Design and validation of siRNAs and shRNAs. Curr Opin Mol Ther. 2009;11:156–64.PubMed
41.
go back to reference Paddison PJ, Hannon GJ. siRNAs and shRNAs: skeleton keys to the human genome. Curr Opin Mol Ther. 2003;5:217–24.PubMed Paddison PJ, Hannon GJ. siRNAs and shRNAs: skeleton keys to the human genome. Curr Opin Mol Ther. 2003;5:217–24.PubMed
Metadata
Title
RBPJ inhibition impairs the growth of lung cancer
Authors
Qun Lv
Ronglin Shen
Jianjun Wang
Publication date
01-05-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-3015-5

Other articles of this Issue 5/2015

Tumor Biology 5/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine