HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner

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art_RABACHINI_HPV16_E7_expression_upregulates_phospholipase_D_activity_and_2018.PDF (2.8 MB)
Citações na Scopus
16
Tipo de produção
article
Data de publicação
2018
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
BIOMED CENTRAL LTD
Autores
RABACHINI, Tatiana
BOCCARDO, Enrique
ANDRADE, Rubiana
PEREZ, Katia Regina
NONOGAKI, Suely
CUCCOVIA, Iolanda Midea
Citação
BMC CANCER, v.18, article ID 485, 8p, 2018
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background: Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer. HPV-16 E6 and E7 expression is essential for induction and maintenance of the transformed phenotype. These oncoproteins interfere with the function of several intracellular proteins, including those controlling the PI3K/AKT/mTOR pathway in which Phospolipase D (PLD) and Phosphatidic acid (PA) play a critical role. Methods: PLD activity was measured in primary human keratinocytes transduced with retroviruses expressing HPV-16 E6, E7 or E7 mutants. The cytostatic effect of rapamycin, a well-known mTOR inhibitor with potential clinical applications, was evaluated in monolayer and organotypic cultures. Results: HPV-16 E7 expression in primary human keratinocytes leads to an increase in PLD expression and activity. Moreover, this activation is dependent on the ability of HPV-16 E7 to induce retinoblastoma protein (pRb) degradation. We also show that cells expressing HPV-16 E7 or silenced for pRb acquire resistance to the antiproliferative effect of rapamycin. Conclusion: This is the first indication that HPV oncoproteins can affect PLD activity. Since PA can interfere with the ability of rapamycin to bind mTOR, the use of combined strategies to target mTOR and PLD activity might be considered to treat HPV-related malignancies.
Palavras-chave
HPV, E7, PLD, Phospholipase, Rapamycin, Phosphatidic acid, PA, mTOR, pRb
URI
https://observatorio.fm.usp.br/handle/OPI/26920
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MDR
Artigos e Materiais de Revistas Científicas - LIM/24
Artigos e Materiais de Revistas Científicas - ODS/03