Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: Roles of p53 and caspase activation

Liu, Yongmin; McKalip, Ann; Herman, Brian

doi:10.1002/(sici)1097-4644(20000801)78:2<334::aid-jcb15>3.0.co;2-f

Cited by 36 publications

(22 citation statements)

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“…25), and the treatment of cervical cancer cell lines with chemotherapeutic compounds such as cisplatin often induces elevated levels of p53 even in the presence of the HPV E6 protein (11,29). It was therefore possible that DHA might be inducing apoptosis by increasing cellular p53 levels.…”

Section: Resultsmentioning

confidence: 99%

Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo

et al. 2005

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Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Because many neoplastic cells (including cervical cancer cells) overexpress the transferrin receptor to increase their iron uptake, we hypothesized that irondependent, antimalarial drugs such as artemisinin might prove useful in treating HPV-infected or transformed cells. We tested three different artemisinin compounds and found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic effects on HPV-immortalized and transformed cervical cells in vitro with little effect on normal cervical epithelial cells. DHA-induced cell death involved activation of the mitochondrial caspase pathway with resultant apoptosis. Apoptosis was p53 independent and was not the consequence of drug-induced reductions in viral oncogene expression. Due to its selective cytotoxicity, hydrophobicity, and known ability to penetrate epithelial surfaces, we postulated that DHA might be useful for the topical treatment of mucosal papillomavirus lesions. To test this hypothesis, we applied DHA to the oral mucosa of dogs that had been challenged with the canine oral papillomavirus. Although applied only intermittently, DHA strongly inhibited viral-induced tumor formation. Interestingly, the DHA-treated, tumor-negative dogs developed antibodies against the viral L1 capsid protein, suggesting that DHA had inhibited tumor growth but not early rounds of papillomavirus replication. These findings indicate that DHA and other artemisinin derivatives may be useful for the topical treatment of epithelial papillomavirus lesions, including those that have progressed to the neoplastic state. (Cancer Res 2005; 65(23): 10854-61)

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Section: Resultsmentioning

confidence: 99%

Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo

et al. 2005

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“…23 However, E6 can sensitize human keratinocytes to apoptosis induced by chemotherapeutic drugs. 24 The most physiological way, however, to trigger programmed cell death is the engagement of CD95 receptor to its ligand (CD95L). 25 This interaction can be mimicked by agonistic anti-CD95 (APO-1) antibodies.…”

Section: When Cervical Carcinoma Cells Were Monitored For Apoptotic Smentioning

confidence: 99%

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

et al. 2001

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When cervical carcinoma cells were monitored for apoptotic signals, HPV18؉ lines were found to be highly sensitive to agonistic CD95 antibodies or recombinant CD95 ligands after co-exposure with CHX (CD95 S ). In contrast, HPV16؉ cervical carcinoma cells and HPV16-immortalized non-malignant human keratinocytes were CD95-resistant (CD95 R ) under equivalent conditions. Somatic cell hybridization between CD95 S and CD95 R cervical carcinoma cell lines revealed that CD95 sensitivity was a dominant trait, which could be correlated with abundant c-Myc and low Bcl-X L expression. Although CD95 R cervical carcinoma cells expressed even higher levels of p53 and CD95 receptor at the surface, resistance could be attributed to the inability to form a functional DISC, necessary for successful transmission of the apoptogenic response. These data indicate that resistance to apoptotic stimuli represents an important immunological escape mechanism during virus-induced carcinogenesis. © Certain HPV types (e.g., HPV16 and HPV18) are etiologically involved in the development of cervical cancer. 1 Their viral oncogenes, E6 and E7, can induce immortalization of primary human keratinocytes, 2,3 which is accompanied by defined changes of the genetic program. For instance, degradation of p53 by E6 4 and E7-mediated induction of unscheduled DNA synthesis via inappropriate release of the transcription factor E2F from pRb 5 disturb not only cell-cycle control 6 but also DNA repair and chromosomal stability. 7 These effects are apparently not sufficient for the progression from pre-cancerous lesions to invasive cervical cancer. Additional events, such as loss of genetic function 8 and/or abrogation of cross-talk between HPV ϩ keratinocytes and effector cells of the immune system, 9 have to take place to permit malignant transformation.Besides known immunological escape mechanisms, such as down-regulation of MHC class I expression 10 and dysfunctional expression of the chemokine/cytokine pattern, 11,12 accumulation of cervical intra-epithelial cell abnormalities could be favored by disturbances in apoptotic signal transduction. 13 Considering tumor formation simply as a result of a numerical imbalance between cell loss (e.g., through immunological elimination) and cell gain (via uncontrolled proliferation and ignorance of cellular homeostasis signals), 14 there is substantial evidence that certain human pathogenic viruses, e.g., Epstein-Barr virus 15 and human T-cell leukemia virus, 16 can selectively interfere with apoptosis. This is mediated either by ablating pro-apoptotic signals or by enhancing factors that prevent programmed cell death. 17 Apoptosis can be achieved by a variety of external signals, e.g., UV light, 18 nutritional depletion, 19 growth factor withdrawal 20 and chemotherapeutic drugs. 21 Although many reports have described the role of E6 and E7 in apoptosis, 22 the results are somewhat contradictory since the apoptotic response apparently depends on the respective model system and/or the nature of the apoptotic stimulu...

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“…Therefore any radiation damage would not be sufficiently repaired, and damaged cells would be more likely to die during mitosis as they progress through the cell cycle. E6 has previously been shown to sensitize mammary epithelial cells, fibroblasts and keratinocytes to chemically induced death (Xu, Meikrantz et al 1995, Hawkins, Demers et al 1996, Liu, McKalip et al 2000, Liu, Zhao et al 2007), but has been reported to have the opposite effect or no effect in other cell types exposed to ionizing radiation or DNA-damaging chemicals (DeWeese, Walsh et al 1997, Hampson, El Hady et al 2001, Shai, Nguyen et al 2007). Thus, the radiosensitizing effect might be specific to a few cell types, including keratinocytes, the natural hosts for HPVs, and be dependent on the E6*I isoform.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Human Papillomavirus E6 Oncogene on the Radiosensitivity of Non-Oropharyngeal Cancer Cells

Hong¹,

Zhang²,

Zhang³

et al. 2017

CCO

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Background:We have previously shown that stable transfection of the human papillomavirus (HPV) E6*I oncogene can sensitize two HPV negative oropharyngeal cancer (OSCC) cell lines to radiation. In the current study, we extended our work on OSCC to determine whether the HPV E6 oncogene can enhance the radiosensitivity of non-OSCC cell lines. Methods:Three non-OSCC cell lines (melanoma, colorectal adenocarcinoma and large cell lung cancer) were stably transfection with the HPV E6 oncogene (E6 total, E6*I and E6*II) and treated with different doses of radiation. Clonogenic assays were used to measure the radiation survival. Results:Following transfection, there was a reduction in the survival of the melanoma cell line after 2 Gy (SF2) from 0.401 (untransfected) to 0.219 (Melanoma-E6 total). This reduction was not evident at higher doses of radiation. There was no significant change in the SF2 of melanoma-E6*I (0.303) and melanoma-E6*II (0.414). The SF2 colorectal adenocarcinoma and large cell lung cancer cell lines did not change significantly after transfection. Conclusions:The radiosensitizing effect of HPV E6 oncogene is cell line specific. We found no clear evidence of a radiosensitising effect of E6 in these three non-OSCC cancer cell lines.

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Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: Roles of p53 and caspase activation

Cited by 36 publications

References 40 publications

Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo

Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

The Effect of Human Papillomavirus E6 Oncogene on the Radiosensitivity of Non-Oropharyngeal Cancer Cells

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