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

Author(s)

Cabeca, Tatiane Karen ^[1] ; Abreu, Alice de Mello ^[1] ; Andrette, Rafael ^[1] ; Lino, Vanesca de Souza ^[1] ; Morale, Mirian Galliote ^{[2, 3]} ; Aguayo, Francisco ^{[4, 5]} ; Termini, Lara ^[3] ; Villa, Luisa Lina ^{[2, 3]} ; Lepique, Ana Paula ^[6] ; Boccardo, Enrique ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, BR-05508900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, BR-01246903 Sao Paulo - Brazil

^[3] ICESP, Ctr Invest Translac Oncol LIM24, Lab Inovacao Canc, BR-01246000 Sao Paulo - Brazil

^[4] Univ Chile, Fac Med, Dept Basic & Clin Oncol, Santiago 8389100 - Chile

^[5] Univ Chile, Adv Ctr Chron Dis ACCDiS, Santiago 8389100 - Chile

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508900 Sao Paulo - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 20, n. 1 JAN 1 2019.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 11/14416-9 - Study of E6 and E7 proteins from HPV16 and HPV6 and its effects on Toll like receptors signaling pathways
• Grantee: Mirian Galliote Morale
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 08/03232-1 - HPV and tumor microenvironment
• Grantee: Luisa Lina Villa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/20002-0 - Study of Synthetic Lethality in cells infected with Human Papillomaviruses (HPV)
• Grantee: Enrique Mario Boccardo Pierulivo
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 08/57889-1 - Institute of Science and Technology to study Diseases Associated with Papillomavirus
• Grantee: Luisa Lina Villa
• Support Opportunities: Research Projects - Thematic Grants