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

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. Metformininduced 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 chemotherapyinduced 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.

FAM57A (Family with Sequence Similarity 57 Member A) Is a Cell-Density-Regulated Protein and Promotes the Proliferation and Migration of Cervical Cancer Cells

“…This observation also emphasizes the importance to control in comparative analyses of cells at hypoxia vs. normoxia (or other conditions differentially affecting cellular proliferation) whether “positive hits” may actually be based on secondary effects, which can result from differences in cell growth, cell density, or other confounding variables. In line with these considerations, siRNA-mediated viral E6/E7 oncogene repression, which exerts strong anti-proliferative effects in HPV-positive cancer cells [ 4 , 33 , 34 ], was also linked to a substantial increase of FAM57A protein levels when compared to control siRNA-treated cells. Yet, silencing E6/E7 expression in FAM57A -expressing cells cultivated at LD conditions did not affect FAM57A levels.…”

“…Next, we investigated whether other anti-proliferative stimuli than hypoxia result in a relative increase of FAM57A protein levels. In cervical cancer cells, such as HPV16-positive SiHa cells, RNAi-mediated silencing of viral E6/E7 oncogene expression exerts strong growth-inhibitory effects and results in the rapid induction of cellular senescence [ 4 , 33 , 34 ]. Notably, compared to control siRNA-transfected cells, which continued to grow and reach high cell densities, FAM57A protein levels were increased when E6/E7 expression was silenced ( Figure 4 a).…”

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

“…Considering HPV-positive HNSCC cells, metformin downregulated the oncoproteins E6 and E7. A downside of this treatment was that cells were induced to enter on quiescence, evading senescence induced by other treatments [124]. Similarly, in OSCC cells, metformin inhibited proliferation but decreased cisplatin toxicity [125], an effect that can be reverted under glucose deprivation conditions [126].…”

Protection by metformin against severe Covid-19: An in-depth mechanistic analysis

“…Effects against prions have also been suggested [22] . A recent publication described MET's inhibition of virus-host interactions in human papillomavirus-positive cancer cells [23] . In people with diabetes, MET use was associated with a significantly reduced risk of infections compared to insulin or sulphonylureas [24] .…”