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HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1

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posted on 13.10.2021, 19:21 by Manuela Antonioli, Benedetta Pagni, Tiziana Vescovo, Rob Ellis, Benjamin Cosway, Francesca Rollo, Veronica Bordoni, Chiara Agrati, Marie Labus, Renato Covello, Maria Benevolo, Giuseppe Ippolito, Max Robinson, Mauro Piacentini, Penny Lovat, Gian Maria Fimia

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC.

Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC).

Funding

This work was supported by the Associazione Italiana per la Ricerca sul Cancro [17404]; Associazione Italiana per la Ricerca sul Cancro [21880]; Cancer Research UK [clinical bursary]; Cancer Research UK [clinical bursary]; European Cooperation in Science and Technology [CA15138]; FP7 People: Marie-Curie Actions [Fellowship]; Fondazione Umberto Veronesi [Fellowship]; Fondazione per la Ricerca sulla Fibrosi Cistica [FFC#8/2018]; Medical Research Council [Molecular pathology Node]; Medical Research Council [Molecular pathology Node]; Ministero della Salute [GR-2013-02359524]; Ministero dell’Istruzione, dell’Università e della Ricerca [20152CB22L]; Regione Lazio [“Gruppi di Ricerca” 2018].

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