Adhesion signaling promotes protease‑driven polyploidization of glioblastoma cells

Mercapide,Javier; Lorico,Aurelio

doi:10.3892/ijmm.2014.1913

Adhesion signaling promotes protease‑driven polyploidization of glioblastoma cells

Authors:
- Javier Mercapide
- Aurelio Lorico
View Affiliations

Affiliations: Cancer Research Center, Roseman University of Health Sciences, Las Vegas, NV, USA
Published online on: August 25, 2014 https://doi.org/10.3892/ijmm.2014.1913
Pages: 1365-1371

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

An increase in ploidy (polyploidization) causes genomic instability in cancer. However, the determinants for the increased DNA content of cancer cells have not yet been fully elucidated. In the present study, we investigated whether adhesion induces polyploidization in human U87MG glioblastoma cells. For this purpose, we employed expression vectors that reported transcriptional activation by signaling networks implicated in cancer. Signaling activation induced by intercellular integrin binding elicited both extracellular signal‑regulated kinase (ERK) and Notch target transcription. Upon the prolonged activation of both ERK and Notch target transcription induced by integrin binding to adhesion protein, cell cultures accumulated polyploid cells, as determined by cell DNA content distribution analysis and the quantification of polynucleated cells. This linked the transcriptional activation induced by integrin adhesion to the increased frequency of polyploidization. Accordingly, the inhibition of signaling decreased the extent of polyploidization mediated by protease‑driven intracellular invasion. Therefore, the findings of this study indicate that integrin adhesion induces polyploidization through the stimulation of glioblastoma cell invasiveness.

View Figures

View References

1	Sluder G and Nordberg JJ: The good, the bad and the ugly: the practical consequences of centrosome amplification. Curr Opin Cell Biol. 16:49–54. 2004. View Article : Google Scholar : PubMed/NCBI
2	Davoli T and de Lange T: The causes and consequences of polyploidy in normal development and cancer. Annu Rev Cell Dev Biol. 27:585–610. 2011. View Article : Google Scholar : PubMed/NCBI
3	Vitale I, Galluzzi L, Senovilla L, Criollo A, Jemaà M, Castedo M and Kroemer G: Illicit survival of cancer cells during polyploidization and depolyploidization. Cell Death Differ. 18:1403–1413. 2011. View Article : Google Scholar : PubMed/NCBI
4	Chakraborty AK, Sodi S, Rachkovsky M, Kolesnikova N, Platt JT, Bolognia JL and Pawelek JM: A spontaneous murine melanoma lung metastasis comprised of host x tumor hybrids. Cancer Res. 60:2512–2519. 2000.PubMed/NCBI
5	Lagarde AE, Donaghue TP, Dennis JW and Kerbel RS: Genotypic and phenotypic evolution of a murine tumor during its progression in vivo toward metastasis. J Natl Cancer Inst. 71:183–191. 1983.PubMed/NCBI
6	Ogle BM, Cascalho M and Platt JL: Biological implications of cell fusion. Nat Rev Mol Cell Biol. 6:567–575. 2005. View Article : Google Scholar : PubMed/NCBI
7	Chen EH, Grote E, Mohler W and Vignery A: Cell-cell fusion. FEBS Lett. 581:2181–2193. 2007. View Article : Google Scholar : PubMed/NCBI
8	Zhou X and Platt JL: Molecular and cellular mechanisms of mammalian cell fusion. Adv Exp Med Biol. 713:33–64. 2011. View Article : Google Scholar : PubMed/NCBI
9	Mercapide J, Anzanello F, Rappa G and Lorico A: Relationship between tumor cell invasiveness and polyploidization. PLoS One. 7:e533642012. View Article : Google Scholar : PubMed/NCBI
10	Lorico A, Mercapide J, Solodushko V, Alexeyev M, Fodstad O and Rappa G: Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma. Cancer Gene Ther. 15:605–615. 2008. View Article : Google Scholar : PubMed/NCBI
11	Yee KL, Weaver VM and Hammer DA: Integrin-mediated signalling through the MAP-kinase pathway. IET Syst Biol. 2:8–15. 2008. View Article : Google Scholar : PubMed/NCBI
12	Campos LS, Decker L, Taylor V and Skarnes W: Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells. J Biol Chem. 281:5300–5309. 2006. View Article : Google Scholar : PubMed/NCBI
13	Conacci-Sorrell M, Kaplan A, Raveh S, Gavert N, Sakurai T and Ben-Ze’ev A: The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation. Cancer Res. 65:11605–11612. 2005. View Article : Google Scholar : PubMed/NCBI
14	Sterling H, Saginario C and Vignery A: CD44 occupancy prevents macrophage multinucleation. J Cell Biol. 143:837–847. 1998. View Article : Google Scholar : PubMed/NCBI
15	Enam SA, Rosenblum ML and Edvardsen K: Role of extracellular matrix in tumor invasion: migration of glioma cells along fibronectin-positive mesenchymal cell processes. Neurosurgery. 42:599–607. 1998. View Article : Google Scholar : PubMed/NCBI
16	Díaz B, Yuen A, Iizuka S, Higashiyama S and Courtneidge SA: Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 201:279–292. 2013.PubMed/NCBI
17	Anand M, van Meter TE and Fillmore HL: Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway. J Neurooncol. 104:679–687. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kunapuli P, Kasyapa CS, Hawthorn L and Cowell JK: LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. J Biol Chem. 279:23151–23157. 2004. View Article : Google Scholar : PubMed/NCBI
19	Lakka SS, Jasti SL, Gondi C, Boyd D, Chandrasekar N, Dinh DH, Olivero WC, Gujrati M and Rao JS: Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. Oncogene. 21:5601–5608. 2002. View Article : Google Scholar : PubMed/NCBI
20	Lin YM, Jan HJ, Lee CC, Tao HY, Shih YL, Wei HW and Lee HM: Dexamethasone reduced invasiveness of human malignant glioblastoma cells through a MAPK phosphatase-1 (MKP-1) dependent mechanism. Eur J Pharmacol. 593:1–9. 2008. View Article : Google Scholar : PubMed/NCBI
21	Sehgal A, Boynton AL, Young RF, Vermeulen SS, Yonemura KS, Kohler EP, Aldape HC, Simrell CR and Murphy GP: Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors. Int J Cancer. 76:451–458. 1998. View Article : Google Scholar : PubMed/NCBI