Short half‐life of HPV16 E6 and E7 mRNAs sensitizes HPV16‐positive tonsillar cancer cell line HN26 to DNA‐damaging drugs

Abstract

Here we show that treatment of the HPV16‐positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan‐induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down‐regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1‐negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half‐life of the HPV16 E6 and E7 mRNAs renders HPV16‐driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

Changes of miRNA Expression Profiles from Cervical-Vaginal Fluid-Derived Exosomes in Response to HPV16 Infection

“…Among the twelve high-risk HPV genotypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), HPV16 is the most carcinogenic HPV type [15]. HPV16 is a small nonenveloped virus with double-stranded DNA as its genetic material [6]. It was reported that E6 and E7, as important functional coding regions of HPV16, were the most responsible oncoproteins for their tumorigenesis [16].…”

“…The changed components of CVF can be taken as the basis for cervical cancer screening by self-testing [5]. Notably, accumulating evidence demonstrated that abnormally high levels of mRNAs, miRNAs, and lncRNAs existed in CVF-derived exosomes [5,6]. With the lipid bilayers, the contents of exosome in CVF can avoid RNase digestion [7].…”

Proteasome Inhibitors Counteract the Effect of Cisplatin in HPV-Positive Squamous Cell Carcinoma in Vitro

“…In fact, it might even be contraindicated to further exploit proteasome inhibition to boost the activity of other cytostatic drug for HPV positive OPSCC patients. An alternative approach previously suggested by us could be to exploit substances that inhibit the transcription of the HPV16 E6 and E7 genes as the E6 and E7 mRNA and proteins are labile and quickly degraded, p53 levels are restored and cause apoptosis of the cancer cells [29]. HN26 cells (50-80% con uent) were treated with the IC50 concentrations of bortezomib (8.9 nmol/L) and cisplatin (0.99 µmol/L [12]).…”

Proteasome inhibitors counteract the effect of cisplatin in an HPV-positive tonsil squamous cell carcinoma in vitro

“…In fact, it might even be contraindicated to further exploit proteasome inhibition to boost the activity of other cytostatic drug for HPV positive OPSCC patients. An alternative approach previously suggested by us could be to exploit substances that inhibit the transcription of the HPV16 E6 and E7 genes as the E6 and E7 mRNA and proteins are labile and quickly degraded, p53 levels are restored and cause apoptosis of the cancer cells [30].…”