Portal de Periódicos da CAPES

Effects of Metformin on the virus/host cell crosstalk in human papillomavirus‐positive cancer cells

2021; Wiley; Volume: 149; Issue: 5 Linguagem: Inglês

10.1002/ijc.33594

1097-0215

Karin Hoppe‐Seyler, Anja L. Herrmann, Antonia Däschle, Bianca J. Kuhn, Tobias D. Strobel, Claudia Lohrey, Julia Bulkescher, Jeroen Krijgsveld, Felix Hoppe‐Seyler,

Virus-based gene therapy research

Abstract Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The viral E6/E7 oncogenes maintain the malignant growth of HPV‐positive cancer cells. Targeted E6/E7 inhibition results in efficient induction of cellular senescence, which could be exploited for therapeutic purposes. Here we show that viral E6/E7 expression is strongly downregulated by Metformin in HPV‐positive cervical cancer and head and neck cancer cells, both at the transcript and protein level. Metformin‐induced E6/E7 repression is glucose and PI3K‐dependent but—other than E6/E7 repression under hypoxia—AKT‐independent. Proteome analyses reveal that Metformin‐induced HPV oncogene repression is linked to the downregulation of cellular factors associated with E6/E7 expression in HPV‐positive cancer biopsies. Notably, despite efficient E6/E7 repression, Metformin induces only a reversible proliferative stop in HPV‐positive cancer cells and enables them to evade senescence. Metformin also efficiently blocks senescence induction in HPV‐positive cancer cells in response to targeted E6/E7 inhibition by RNA interference. Moreover, Metformin treatment enables HPV‐positive cancer cells to escape from chemotherapy‐induced senescence. These findings uncover profound effects of Metformin on the virus/host cell interactions and the phenotype of HPV‐positive cancer cells with implications for therapy‐induced senescence, for attempts to repurpose Metformin as an anticancer agent and for the development of E6/E7‐inhibitory therapeutic strategies.