Abstract
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.
Highlights
Human papillomavirus (HPV) infection is linked with several cancers such as cervix and head and neck carcinomas (Killock, 2015; Lehtinen & Dillner, 2013)
The data suggest that the growth of HPV(+) UM-SCC-47-derived head and neck squamous cell carcinoma (HNSCC) xenografts was inhibited in response to cisplatin (~75% inhibition), whereas there was no detectable tumor suppression when HPV(À) UM-SCC-22A-derived xenografts were treated with this drug in Severe combined immunodeficient (SCID) mice (Fig EV1A and B)
To identify the downstream mediators of HPV-early protein 7 (E7)/retinoblastoma protein (RB) signaling in enhancing ceramide-mediated lethal mitophagy, we investigated the roles of E2F proteins, the canonical downstream targets of RB
Summary
Human papillomavirus (HPV) infection is linked with several cancers such as cervix and head and neck carcinomas (Killock, 2015; Lehtinen & Dillner, 2013). HPV infection is associated with improved survival outcome in response to chemo-radiotherapy for patients with head and neck squamous cell carcinoma (HNSCC), and not in patients with HPV(+) cervical cancers (Fakhry et al, 2008; Ang et al, 2010). Molecular mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Whether induction of ceramide-mediated lethal mitophagy is involved in increased cell death in HPV(+) HNSCC in response to therapeutic treatment and cellular stress has not been described previously. EMBO Molecular Medicine response of HNSCC versus cervical cancer cells to chemotherapymediated cellular stress by ceramide-dependent lethal mitophagy
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