title: Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis.
abstract: Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 °C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell-cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Arlene L
authors.initials: AL
authors.lastname: Oei
authors.affiliation: Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Caspar M
authors.initials: CM
authors.lastname: van Leeuwen
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: ten Cate
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Hans M
authors.initials: HM
authors.lastname: Rodermond
authors.affiliation: Department of Gynecologic Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marrije R
authors.initials: MR
authors.lastname: Buist
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lukas J A
authors.initials: LJ
authors.lastname: Stalpers
authors.affiliation: Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Crezee
authors.affiliation: Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: H Petra
authors.initials: HP
authors.lastname: Kok
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands. Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. N.A.Franken@amc.uva.nl.
authors.forename: Nicolaas A P
authors.initials: NA
authors.lastname: Franken
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000302:isolation & purification / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications* / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53