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

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dc.citation.volumev. 18
dc.contributor.authorRabachini, Tatiana
dc.contributor.authorBoccardo, Enrique
dc.contributor.authorAndrade, Rubiana
dc.contributor.authorPerez, Katia Regina [UNIFESP]
dc.contributor.authorNonogaki, Suely
dc.contributor.authorCuccovia, Iolanda Midea
dc.contributor.authorVilla, Luisa Lina
dc.coverageLondon
dc.date.accessioned2020-07-20T16:30:59Z
dc.date.available2020-07-20T16:30:59Z
dc.date.issued2018
dc.description.abstractBackground: 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.en
dc.description.affiliationHosp Sirio Libanes, Ludwig Inst Canc Res, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Escola Paulista Med, Dept Biofis, Sao Paulo, SP, Brazil
dc.description.affiliationAdolfo Lutz Inst, Ctr Patol, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo, SP, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Escola Paulista Med, Dept Biofis, Sao Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipLudwig Institute for Cancer Research
dc.description.sponsorshipFundacao de Amparo a pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorshipCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Pesquisa e Desenvolvimento (CNPq)
dc.description.sponsorshipIDFAPESP: 2003/14008-9
dc.description.sponsorshipIDFAPESP: 2010/20002-0
dc.description.sponsorshipIDFAPESP: 05/59142-2
dc.description.sponsorshipIDFAPESP: 2008/03232-1
dc.description.sponsorshipIDFAPESP: 2008/57889-1
dc.description.sponsorshipIDCNPq: 573799/2008-3
dc.description.sponsorshipIDCNPq: 480552-2011
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.1186/s12885-018-4392-8
dc.identifier.citationBmc Cancer. London, v. 18, p. -, 2018.
dc.identifier.doi10.1186/s12885-018-4392-8
dc.identifier.fileWOS000431267000015.pdf
dc.identifier.issn1471-2407
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55625
dc.identifier.wosWOS:000431267000015
dc.language.isoeng
dc.publisherBiomed Central Ltd
dc.relation.ispartofBmc Cancer
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectHPVen
dc.subjectE7en
dc.subjectPLDen
dc.subjectPhospholipaseen
dc.subjectRapamycinen
dc.subjectPhosphatidic aciden
dc.subjectPAen
dc.subjectmTORen
dc.subjectpRben
dc.titleHPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manneren
dc.typeinfo:eu-repo/semantics/article
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