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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Critical role of CDK11p58 in human breast cancer growth and angiogenesis

Authors: Yayun Chi, Sheng Huang, Haojie Peng, Mengying Liu, Jun Zhao, Zhiming Shao, Jiong Wu

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

A capillary network is needed in cancer growth and metastasis. Induction of angiogenesis represents one of the major hallmarks of cancer. CDK11p58, a Ser/Thr kinase that belongs to the Cell Division Cycle 2-like 1 (CDC2L1) subfamily is associated with cell cycle progression, tumorigenesis, sister chromatid cohesion and apoptotic signaling. However, its role in breast cancer proliferation and angiogenesis remains unclear.

Methods

Tumorigenicity assays and blood vessel assessment in athymic mice were used to assess the function of CDK11p58 in tumor proliferation and angiogenesis. CCK-8 assay was used to detect breast cancer cell growth. Immunohistochemistry was used to detect the expression of vascular endothelial growth factor (VEGF), CD31 and CD34 in CDK11 positive patient breast cancer tissues. Dual-Luciferase array was used to analyze the function of CDK11p58 in the regulation of VEGF promoter activity. Western blot was used to detect related protein expression levels.

Results

CDK11p58 inhibited breast cancer growth and angiogenesis in breast cancer cells and in nude mice transplanted with tumors. Immunohistochemistry confirmed that CDK11p58 was negatively associated with angiogenesis-related proteins such as VEGF, CD31 and CD34 in breast cancer patients. Real-time PCR and dual-luciferase assay showed CDK11p58 inhibited the mRNA levels of VEGF and the promoter activity of VEGF. As CDK11p58 is a Ser/Thr kinase, the kinase-dead mutant failed to inhibit VEGF mRNA and promoter activity. Western blot analysis showed the same pattern of related protein expression. The data suggested angiogenesis inhibition was dependent on CDK11p58 kinase activity.

Conclusion

This study indicates that CDK11p58 inhibits the growth and angiogenesis of breast cancer dependent on its kinase activity.
Appendix
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Literature
1.
2.
Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.CrossRefPubMed
3.
Park MS, Dong SM, Kim BR, Seo SH, Kang S, Lee EJ, et al. Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts. Oncotarget. 2014;5(13):4929–34.CrossRefPubMedPubMedCentral
4.
5.
Chen PC, Cheng HC, Wang J, Wang SW, Tai HC, Lin CW, et al. Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment. Oncotarget. 2014;5(6):1595–608.CrossRefPubMedPubMedCentral
6.
Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267(16):10931–4.PubMed
7.
Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996;56(9):2013–6.PubMed
8.
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84(24):1875–87.CrossRefPubMed
9.
Zhang S, Cai M, Zhang S, Xu S, Chen S, Chen X, et al. Interaction of p58 (PITSLRE), a G2/M-specific protein kinase, with cyclin D3. J Biol Chem. 2002;277(38):35314–22.CrossRefPubMed
10.
Franck N, Montembault E, Rome P, Pascal A, Cremet JY, Giet R. CDK11 (p58) is required for centriole duplication and Plk4 recruitment to mitotic centrosomes. PLoS ONE. 2011;6(1):e14600.CrossRefPubMedPubMedCentral
11.
Petretti C, Savoian M, Montembault E, Glover DM, Prigent C, Giet R. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. Embo Rep. 2006;7(4):418–24.PubMedPubMedCentral
12.
Zong H, Chi Y, Wang Y, Yang Y, Zhang L, Chen H, et al. Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol Cell Biol. 2007;27(20):7125–42.CrossRefPubMedPubMedCentral
13.
Wang Y, Zong H, Chi Y, Hong Y, Yang Y, Zou W, et al. Repression of estrogen receptor alpha by CDK11p58 through promoting its ubiquitin-proteasome degradation. J Biochem. 2009;145(3):331–43.CrossRefPubMed
14.
15.
Chi Y, Huang S, Wang L, Zhou R, Wang L, Xiao X, et al. CDK11p58 inhibits ERalpha-positive breast cancer invasion by targeting integrin beta3 via the repression of ERalpha signaling. BMC Cancer. 2014;14:577.CrossRefPubMedPubMedCentral
16.
Terzuoli E, Meini S, Cucchi P, Catalani C, Cialdai C, Maggi CA, et al. Antagonism of bradykinin B2 receptor prevents inflammatory responses in human endothelial cells by quenching the NF-kB pathway activation. PLoS ONE. 2014;9(1):e84358.CrossRefPubMedPubMedCentral
17.
Jin W, Chen BB, Li JY, Zhu H, Huang M, Gu SM, et al. TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway. Mol Cell Biol. 2012;32(1):50–63.CrossRefPubMedPubMedCentral
18.
Chi Y, Zhang C, Zong H, Hong Y, Kong X, Liu H, et al. Thr-370 is responsible for CDK11 (p58) autophosphorylation, dimerization, and kinase activity. J Biol Chem. 2011;286(3):1748–57.CrossRefPubMed
19.
Lam HM, Suresh BC, Wang J, Yuan Y, Lam YW, Ho SM, et al. Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion. Mol Cell Endocrinol. 2012;358(1):27–35.CrossRefPubMedPubMedCentral
20.
Keyhani E, Muhammadnejad A, Behjati F, Sirati F, Khodadadi F, Karimlou M, et al. Angiogenesis markers in breast cancer--potentially useful tools for priority setting of anti-angiogenic agents. Asian Pac J Cancer Prev. 2013;14(12):7651–6.CrossRefPubMed
21.
Shim HJ, Kim SH, Kang BJ, Choi BG, Kim HS, Cha ES, et al. Breast cancer recurrence according to molecular subtype. Asian Pac J Cancer Prev. 2014;15(14):5539–44.CrossRefPubMed
22.
Ahmad A, Sethi S, Chen W, Ali-Fehmi R, Mittal S, Sarkar FH. Up-regulation of microRNA-10b is associated with the development of breast cancer brain metastasis. Am J Transl Res. 2014;6(4):384–90.PubMedPubMedCentral
23.
Subramonian D, Raghunayakula S, Olsen JV, Beningo KA, Paschen W, Zhang XD. Analysis of Changes in SUMO-2/3 Modification during Breast Cancer Progression and Metastasis. J Proteome Res. 2014;13(9):3905–18.CrossRefPubMed
24.
Mokhtar M, Tadokoro Y, Nakagawa M, Morimoto M, Takechi H, Kondo K, Tangoku A: Triple assessment of sentinel lymph node metastasis in early breast cancer using preoperative CTLG, intraoperative fluorescence navigation and OSNA. Breast Cancer 2014, Jul 29. [Epub ahead of print].
25.
Dimova I, Popivanov G, Djonov V. Angiogenesis in cancer - general pathways and their therapeutic implications. J BUON. 2014;19(1):15–21.PubMed
26.
Chakraborty S, Adhikary A, Mazumdar M, Mukherjee S, Bhattacharjee P, Guha D, et al. Capsaicin-Induced Activation of p53-SMAR1 Auto-Regulatory Loop Down-Regulates VEGF in Non-Small Cell Lung Cancer to Restrain Angiogenesis. PLoS ONE. 2014;9(6):e99743.CrossRefPubMedPubMedCentral
27.
Chen S, Yin X, Zhu X, Yan J, Ji S, Chen C, et al. The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis. J Biol Chem. 2003;278(22):20029–36.CrossRefPubMed
28.
Yokoyama H, Gruss OJ, Rybina S, Caudron M, Schelder M, Wilm M, et al. Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assembly rate. J Cell Biol. 2008;180(5):867–75.CrossRefPubMedPubMedCentral
29.
Hu D, Valentine M, Kidd VJ, Lahti JM. CDK11 (p58) is required for the maintenance of sister chromatid cohesion. J Cell Sci. 2007;120(Pt 14):2424–34.CrossRefPubMed
30.
Yun X, Wu Y, Yao L, Zong H, Hong Y, Jiang J, et al. CDK11 (p58) protein kinase activity is associated with Bcl-2 down-regulation in pro-apoptosis pathway. Mol Cell Biochem. 2007;304(1–2):213–8.CrossRefPubMed
31.
Wilkinson S, Croft DR, O’Prey J, Meedendorp A, O’Prey M, Dufes C, et al. The cyclin-dependent kinase PITSLRE/CDK11 is required for successful autophagy. Autophagy. 2011;7(11):1295–301.CrossRefPubMedPubMedCentral
32.
Kong X, Gan H, Hao Y, Cheng C, Jiang J, Hong Y, et al. CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression. J Biochem. 2009;146(3):417–27.CrossRefPubMed
33.
Zhang X, Xu WH, Ge YL, Hou L, Li Q. Effect of siRNA transfection targeting VEGF gene on proliferation and apoptosis of human breast cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2007;23(1):14–7.PubMed
34.
Ge YL, Zhang X, Zhang JY, Hou L, Tian RH. The mechanisms on apoptosis by inhibiting VEGF expression in human breast cancer cells. Int Immunopharmacol. 2009;9(4):389–95.CrossRefPubMed
35.
Zhang Q, Gan H, Cheng Z, Zhao S, Chen C, Jiang C, et al. 2-Deoxy-D-glucose combined with Taxol inhibits VEGF expression and induces apoptosis in orthotopically transplanted breast cancer in C3H mice. Nan Fang Yi Ke Da Xue Xue Bao. 2014;34(2):193–6.PubMed
36.
Sapino A, Bongiovanni M, Cassoni P, Righi L, Arisio R, Deaglio S, et al. Expression of CD31 by cells of extensive ductal in situ and invasive carcinomas of the breast. J Pathol. 2001;194(2):254–61.CrossRefPubMed
37.
Righi L, Deaglio S, Pecchioni C, Gregorini A, Horenstein AL, Bussolati G, et al. Role of CD31/platelet endothelial cell adhesion molecule-1 expression in in vitro and in vivo growth and differentiation of human breast cancer cells. Am J Pathol. 2003;162(4):1163–74.CrossRefPubMedPubMedCentral
Metadata
Title
Critical role of CDK11p58 in human breast cancer growth and angiogenesis
Authors
Yayun Chi
Sheng Huang
Haojie Peng
Mengying Liu
Jun Zhao
Zhiming Shao
Jiong Wu
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1698-7

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