E6 Oncoproteins from High-Risk Human Papillomavirus Induce Mitochondrial Metabolism in a Head and Neck Squamous Cell Carcinoma Model

Abstract

Head and neck squamous cell carcinoma (HNSCC) cells that are positive for human papillomavirus (HPV+) favor mitochondrial metabolism rather than glucose metabolism. However, the involvement of mitochondrial metabolism in HNSCC HPV+ cells is still unknown. The aim of this work was to evaluate the role of E6 oncoproteins from HPV16 and HPV18 in the mitochondrial metabolism in an HNSCC model. We found that E6 from both viral types abates the phosphorylation of protein kinase B-serine 473 (pAkt), which is associated with a shift in mitochondrial metabolism. E6 oncoproteins increased the levels of protein subunits of mitochondrial complexes (I to IV), as well as the ATP synthase and the protein levels of the voltage dependent anion channel (VDAC). Although E6 proteins increased the basal and leak respiration, the ATP-linked respiration was not affected, which resulted in mitochondrial decoupling. This increase in leak respiration was associated to the induction of oxidative stress (OS) in cells expressing E6, as it was observed by the fall in the glutathione/glutathione disulfide (GSH/GSSG) rate and the increase in reactive oxygen species (ROS), carbonylated proteins, and DNA damage. Taken together, our results suggest that E6 oncoproteins from HPV16 and HPV18 are inducers of mitochondrial metabolism.

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…None of these genes were associated with altered survival in HPV-HNSCC, reinforcing the concept that HPV+ and HPV-HNSCC are distinct tumour entities [7][8][9]23]. This is not unexpected, as E6 from HPV16 and HPV18 can increase the expression of mitochondrial cellular respiration genes in a head and neck cancer cell line [24], which matches our observation of increased expression of these genes in HPV+ HNSCCs when compared to HPV-HNSCCs. In addition, E6 and E7 may also be responsible for perturbing glycolysis in HPV+ cervical cancer cells [25,26], which could explain our observation of increased expression of glycolytic genes in HPV+ HNSCC as compared to normal control tissues.…”

ATP synthase modulation leads to an increase of spare respiratory capacity in HPV associated cancers

“…It has previously been described that high-risk alphaHPV early proteins interact with mitochondria 19 . Most recently it has further been demonstrated, that the E6 protein of high-risk alphaHPVs induces the mitochondrial metabolism by increasing the protein levels of various mitochondrial complexes 20 . Here, we now show that E7 of HPV8, HPV11 and HPV16 all interact with varying affinity with the mitochondrial ATP synthase subunit ATP5B, which may therefore represent a conserved interaction across alpha and beta HPV.…”

“…Cruz-Gregorio et al recently showed that HPV16 increases protein levels of subunits of mitochondrial complex I-IV as well as the ATP synthase, leading to increased mitochondrial mass. Furthermore, E6 thus increases basal and leak respiration, which was associated with oxidative stress by increasing the amount of reactive oxygen species without having an effect on ATP-linked mitochondrial activity 20 . From these results the authors concluded that this may partially explain why HPV positive OPSCC are more radiosensitive due to oxidative stress and the resulting DNA damage and the susceptibility to ionizing radiation.…”

Redox‐sensitive signalling pathways regulated by human papillomavirus in HPV‐related cancers

“…The latter increases mitochondrial metabolism; however, ROS levels also augment, producing OS and DNA damage. 72 In cervical cancer, HR-HPV16 E7 activates Akt to induce pirin protein. Pirin activates nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) to protect against OS.…”

“…HR-HPV proteins can bind and modify the different functions of mitochondria and the signalling pathways associated with the functioning of these organelles. 1,72 For instance, it showed that in HPV negative cervical cancer cells, HR-HPV16 E6* induce SOD2 and GPX 1/2 overexpression, OS and DNA damage.…”