Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells

Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells

Author de Sousa Mesquita, Ana Paula Autor UNIFESP Google Scholar
Lopes, Silvana de Araujo Autor UNIFESP Google Scholar
Pernambuco Filho, Paulo Castanho A. Autor UNIFESP Google Scholar
Nader, Helena B. Autor UNIFESP Google Scholar
Lopes, Carla Cristina Autor UNIFESP Google Scholar
Abstract Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix. Anoikis resistance is a critical mechanism in tumor metastasis. Cancer cells deregulate and adapt their metabolism to survive in the absence of adhesion, spreading metastases to distant organs. These adaptations include abnormal regulation of growth factor receptors activating prosurvival signaling pathways, such as the Ras/ERK and PI3K/Akt pathways, and extracellular matrix remodeling, leading to metastasis by an increase of invasiveness and inhibiting anoikis. This study investigates the possible involvement of ECM components and signaling pathways in the regulation of resistance to anoikis in endothelial cells (EC). Endothelial cells submitted to stressful conditions by blocking adhesion to substrate (anoikis resistance) display an up-regulation of Ras/ERK and PI3k/Akt pathways by high expression of Ras, ERK, PI3K (p110 alpha) and Akt (Thr 308). After ERK and PI3K inhibiting, all EC-derived cell lines studied showed lower growth, a decrease in invasive potential and a higher rate of apoptosis. Furthermore, anoikis-resistant cell lines display a decrease in the expression of fibronectin, collagen IV and hyaluronic acid and an increase in the expression of laminin, perlecan, alpha v, beta 3, alpha 5 and beta 1 integrins subunits, hyaluronidades 1, 2 and 3 and metalloproteinases 2 and 9. These results indicate that the acquisition of anoikis resistance induced remodeling of the extracellular matrix and overexpression of the PI3K/Akt and Ras/ERK pathway components. Acquisition of resistance to anoikis is a potentially crucial step in endothelial cell transformation.
Keywords Anoikis
Ras/ERK and PI3K/Akt pathways
Extracellular matrix remodeling
Endothelial cells
Language English
Sponsor Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP)
Equipamentos Multiusuario (EMU-FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES)
Financiadora de Estudos e Projetos (FINEP), Brazil
Date 2017
Published in Apoptosis. Dordrecht, v. 22, n. 9, p. 1116-1137, 2017.
ISSN 1360-8185 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 1116-1137
Origin http://dx.doi.org/10.1007/s10495-017-1392-0
Access rights Closed access
Type Article
Web of Science ID WOS:000407899800005
URI http://repositorio.unifesp.br/handle/11600/51352

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