Details

Autor(en) / Beteiligte

• Thomas, Raquela J
• Oleinik, Natalia
• Panneer Selvam, Shanmugam
• Vaena, Silvia G
• Dany, Mohammed
• Nganga, Rose N
• Depalma, Ryan
• Baron, Kyla D
• Kim, Jisun
• Szulc, Zdzislaw M
• Ogretmen, Besim

Titel

HPV/E7 induces chemotherapy‐mediated tumor suppression by ceramide‐dependent mitophagy

Ist Teil von

• EMBO molecular medicine, 2017-08, Vol.9 (8), p.1030-1051

Ort / Verlag

Germany: John Wiley & Sons, Inc

Erscheinungsjahr

2017

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Human papillomavirus (HPV) infection is linked to improved survival in response to chemo‐radiotherapy for patients with oropharynx head and neck squamous cell carcinoma (HNSCC). However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Here, using molecular, pharmacologic and genetic tools, we show that HPV early protein 7 (E7) enhances ceramide‐mediated lethal mitophagy in response to chemotherapy‐induced cellular stress in HPV‐positive HNSCC cells by selectively targeting retinoblastoma protein (RB). Inhibition of RB by HPV‐E7 relieves E2F5, which then associates with DRP1, providing a scaffolding platform for Drp1 activation and mitochondrial translocation, leading to mitochondrial fission and increased lethal mitophagy. Ectopic expression of a constitutively active mutant RB, which is not inhibited by HPV‐E7, attenuated ceramide‐dependent mitophagy and cell death in HPV(+) HNSCC cells. Moreover, mutation of E2F5 to prevent Drp1 activation inhibited mitophagy in HPV(+) cells. Activation of Drp1 with E2F5‐mimetic peptide for inducing Drp1 mitochondrial localization enhanced ceramide‐mediated mitophagy and led to tumor suppression in HPV‐negative HNSCC‐derived xenograft tumors in response to cisplatin in SCID mice. Synopsis HPV infection increases the risk of head and neck squamous cell carcinoma (HNSCC), but also improves sensitivity to therapy. Here, HPV infection is shown to enhance HNSCC cell death by inducing ceramide‐dependent lethal mitophagy. HPV16‐E7 selectively mediates HNSCC cell death via activation of cytoplasmic E2F5 function, liberated by targeting retinoblastoma protein. Activated E2F5 binds and stabilizes Drp1 oligomers as a scaffolding molecule, inducing mitochondrial translocation of Drp1 and mitochondrial fission. E2F5‐Drp1‐mediated mitochondrial fission enhances CerS1/ceramide‐dependent mitophagy and HNSCC cell death. Inhibition of E2F5‐Drp1 complex by site‐directed mutagenesis of E2F5 attenuates HPV‐E7/ceramide‐mediated lethal mitophagy in response to cisplatin in HPV(+) HNSCC cells. Restoring Drp1 activation using an E2F5‐peptide mimetic increases mitochondrial Drp1 localization, enhancing ceramide‐dependent mitophagy and cisplatin‐mediated tumor suppression in HPV(−) HNSCC in situ and in vivo without pathologic HPV infection. HPV infection increases the risk of head and neck squamous cell carcinoma (HNSCC), but also improves sensitivity to therapy. Here, HPV infection is shown to enhance HNSCC cell death by inducing ceramide‐dependent lethal mitophagy.