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

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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 (p110α) 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, αv, β3, α5 and β1 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.

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Acknowledgements

Supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP); Equipamentos Multiusuário (EMU—FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES) and Financiadora de Estudos e Projetos (FINEP), Brazil.

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Author notes

  1. Ana Paula de Sousa Mesquita and Silvana de Araújo Lopes have contributed equally to this work.

Authors and Affiliations

  1. Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil

    Ana Paula de Sousa Mesquita, Silvana de Araújo Lopes, Paulo Castanho A. Pernambuco Filho & Carla Cristina Lopes

  2. Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Ana Paula de Sousa Mesquita, Silvana de Araújo Lopes, Paulo Castanho A. Pernambuco Filho, Helena B. Nader & Carla Cristina Lopes

Authors
  1. Ana Paula de Sousa Mesquita
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  2. Silvana de Araújo Lopes
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  3. Paulo Castanho A. Pernambuco Filho
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  4. Helena B. Nader
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  5. Carla Cristina Lopes
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Correspondence to Carla Cristina Lopes.

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de Sousa Mesquita, A.P., de Araújo Lopes, S., Pernambuco Filho, P.C. et al. Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells. Apoptosis 22, 1116–1137 (2017). https://doi.org/10.1007/s10495-017-1392-0

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  • DOI: https://doi.org/10.1007/s10495-017-1392-0

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