HPV-Mediated Resistance to TNF and TRAIL Is Characterized by Global Alterations in Apoptosis Regulatory Factors, Dysregulation of Death Receptors, and Induction of ROS/RNS

• Published in: International journal of molecular sciences 2019-01, Vol.20 (1), p.198
• Main Authors: Cabeça, Tatiane Karen, de Mello Abreu, Alice, Andrette, Rafael, de Souza Lino, Vanesca, Morale, Mirian Galliote, Aguayo, Francisco, Termini, Lara, Villa, Luisa Lina, Lepique, Ana Paula, Boccardo, Enrique
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis Regulatory Proteins - metabolism; Cell cycle; Cell growth; Cervical cancer; Cervix; Cytokines; Death receptors; Down-Regulation - drug effects; Drug Resistance, Neoplasm - drug effects; Gene expression; Genomes; HeLa Cells; Human papillomavirus; Humans; Inflammation; Inflammation Mediators - metabolism; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - virology; Membrane Potential, Mitochondrial - drug effects; NF-kappa B - metabolism; NF-κB protein; Oncogenes; Papillomaviridae - drug effects; Papillomaviridae - genetics; Papillomaviridae - physiology; Proteins; Reactive Nitrogen Species - metabolism; Reactive Oxygen Species - metabolism; Receptors, Death Domain - metabolism; Receptors, Tumor Necrosis Factor, Type I - metabolism; Risk analysis; Risk factors; Signal Transduction - drug effects; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Tumor cell lines; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Viral infections; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20010198

Persistent infection with high-risk human papilloma virus (HR-HPV) is the main risk factor for the development of invasive cervical cancer although is not sufficient to cause cervical cancer. Several host and environmental factors play a key role in cancer initiation/progression, including cytokines and other immune-response mediators. Here, we characterized the response to the individual and combined action of the pro-inflammatory cytokines tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) on HPV-transformed cells and human keratinocytes ectopically expressing E6 and E7 early proteins from different HPV types. We showed that keratinocytes expressing HPV early proteins exhibited global alterations in the expression of proteins involved in apoptosis regulation/execution, including TNF and TRAIL receptors. Besides, we provided evidence that TNF receptor 1 (TNFR1) was down-regulated and may be retained in the cytoplasm of keratinocytes expressing HPV16 oncoproteins. Finally, fluorescence analysis demonstrated that cytokine treatment induced the production and release of reactive oxygen and nitrogen species (ROS/RNS) in cells expressing HPV oncogenes. Alterations in ROS/RNS production and apoptosis regulatory factors expression in response to inflammatory mediators may favor the accumulation of genetic alterations in HPV-infected cells. Altogether, our results suggested that these events may contribute to lesion progression and cancer onset.