Professor & Associate Dean
Division of Biochemistry
School of Medicine
Loma Linda University
Loma Linda, CA 92350
HPV and Cervical Cancer
Cervical cancer is the second most common cancer for women worldwide, with a mortality rate of approximately 50 percent. This disease is almost always caused by high-risk strains of the human papillomavirus, a sexually transmitted agent, and disproportionately affects minority populations. In men, the most common HPV-associated cancer is cancer of the head and neck. HPV codes for E6 and E7, two oncogenes that work together to transform cells and cause cancer. The Duerksen-Hughes laboratory has discovered that one of the ways in which E6 contributes to HPV oncogenicity is by preventing host cells from responding to signals, such as those generated during an immune response or chemotherapy, that would normally signal the virus-infected cell to die.
E6 functions, at least in part, by protecting the cells that express it from host-generated apoptotic responses such as those triggered by TNF, Fas, and TRAIL. Each of these apoptotic pathways involves multiple signaling molecules. We discovered that E6 binds to several of these molecules, thereby inhibiting transmission of the apoptotic signal. This makes the HPV-positive cells resistant to killing by both the host’s normal defenses and by chemo- and radiotherapy. To develop better options for these patients, we developed and employed a bead-based approach to screen several small molecule libraries for candidates capable of blocking the interactions between the E6 oncoprotein and its cellular partners. This resulted in the discovery of multiple lead candidates, several of which proved effective in cell-based systems. We were then able to move to in vivo testing, funded by an SBIR grant to a small company which I founded.
Normally, the HPV virus exists in cells as an episome and does not integrate. In rare cases, however, integration can occur in such a way as to enable increased expression of the E6 and E7 oncogenes, thereby setting the stage for cancer formation. A second focus of our studies is to understand how and why integration sometimes happens, and to find ways to prevent it. Integration requires breaks in both the viral episome and the human genome, suggesting that events that cause breaks in DNA are likely to lead to increased integration. Oxidative stress is a likely candidate for causing these breaks, and can be caused by both environmental and viral factors. We have found that integration frequency can be increased by agents that increase oxidative stress, and decreased by agents that reduce that stress. These findings suggest strategies to prevent the integration of the HPV episome, and consequently the development of HPV-associated cancers.
Molecular Fingerprints of Health
More recently, our laboratory has begun studying the mechanisms through which the rate of biological aging can be modulated by factors such as diet and activity. Initial findings suggest that lifestyle and psychosocial factors can modulate both telomere length and the pattern of DNA methylation, enabling us to begin the process of tracing the mechanistic events that link environmental factors and lifestyle choices to either accelerated or decelerated aging. This project carries the promise of finding ways to improve the health and longevity of all.
- Miles, F.J., A. Mashchak, V. Filippov, M. J. Orlich, P. Duerksen-Hughes, X. Chen, C. Wang, K. Siegmund and G. E. Fraser. DNA methylation profiles of vegans and non-vegetarians in the Adventist Health Study-2 Cohort. Nutrients 12:E3697, 2020. PMID: 33266012.
- Katerji, M., M. Filippova, Y. C. Wongworawat, S. Siddighi, S. Bashkirova and P. J. Duerksen-Hughes. Oxidative stress markers in patient-derived non-cancerous cervical tissues and cells. Sci. Rep. 10:19044, 2020. PMID: 33149215.
- Knutsen, R., V. Filippov, S. F. Knutsen, G. E. Fraser, J. Lloren, D. Juma and P. Duerksen-Hughes. Cold parenting is associated with cellular aging in offspring: A retrospective study. Biological Psychology 145:142-149, 2019. PMID: 31014776.
- Evans, W., M. Filippova, V. Filippov, S. Bashkirova, G. Zhang, M. E. Reeves and P. J. Duerksen-Hughes. Overexpression of HPV16 E6* Alters -Integrin and Mitochondrial Dysfunction Pathways in Cervical Cancer Cells. Cancer Genomics & Proteomics 13:259-73, 2016. PMID: 27365376.
- Chen Wongworawat, Y., M. Filippova, V. M. Williams, V. Filippov, P. J. Duerksen-Hughes. Chronic oxidative stress increases the integration frequency of foreign DNA and human papillomavirus 16 in human keratinocytes. Am. J. Cancer Research 6:684-680, 2016. PMID: 27186429.
- Yuan, C.-H., M. Filippova, J. L. Krstenansky and P. Duerksen-Hughes. Flavonol and Imidazole Derivatives Block HPV16 E6 Activities and Reactive Apoptotic Pathways in HPV+ Cells. Cell Death & Disease 7:2060-2072, 2016. PMID: 26794656.
- Williams, V. M., M. Filippova, V. Filippov, K. J. Payne and P. J. Duerksen-Hughes. HPV 16 E6* induces oxidative stress and DNA damage. J. Virology 88:6751-6761, 2014. PMID: 24696478. Selected for a JVI Spotlight Feature.
- Filiuppova, M., W. Evans, R. Aragon, V. Filippov, V. Williams, L. Hong, M. E. Reeves, and P. J. Duerksen-Hughes. The Small splice variant of HPV16 E6, E6*, reduces tumor formation in cervical carcinoma xenografts. Virology. 450-451:153-164, 2014. PMID: 24503078
- Filippova, M., V. Filippov, W. M. Williams, K. Zhang, A. Kokoza, S. Bashkirova and P. J. Duerksen-Hughes. Cellular levels of oxidative stress affect the response of cervical cancer cells to chemotherapeutic agents. Biomed. Res. Int. 2014:57659, 2014. PMID: 25478571
- Yuan, C.-H., M. Filippova, S. S. Tungteakkhun, P. J. Duerksen-Hughes and J. L. Krstenansky. Small molecule inhibitors of the HPV16-E6 interaction with caspase 8. Bioorganic and Medicinal Chemistry Letters, 22:2125-2129. 2012. PMID: 22300659
- Filippov, V., M.A. Song, K. Zhang, H. V. Vinters, S. Tung, W. M. Kirsch, J. Yang, and P. J. Duerksen-Hughes. Increased Ceramide in brains with Alzheimer’s and other neurodegenerative diseases. Journal of Alzheimer’s Disease, 29:537-547, 2012. PMID: 22258513
- Haynes, T.-A. S., V. Filippov, M. Filippova, J. Yang, K. Zhang, and P. J. Duerksen-Hughes. DNA damage induces down-regulation of UDP-Glucose Glucosyltransferase, increases ceramide levels and triggers apoptosis in p53-deficient cancer cells. BBA – Molecular and Cell Biology of Lipids, 1821:943-953, 2012. PMID: 22349266
- Whitaker, E. L., V. Filippov, M. Filippova, C. F. Guerrero-Juarez, and P. J. Duerksen-Hughes. Splice variants of mda-7/IL-24 differentially affect survival and induce apoptosis in U2OS cells. Cytokine, 56:272-281, 2011. PMID: 21843952
- Tungteakkhun, S. S., M. Filippova, N. Fodor and P. J. Duerksen-Hughes. The Full Length Isoform of HPV 16 E6 and its Splice Variant E6* Bind to Different Sites on Procaspase 8 DED. J. Virol. 84:1453-1463, 2010. PMID: 19906919
- Filippova, M., V. A. Filippov, M. Kagoda, T. Garnett, N. Fodor and P. J. Duerksen-Hughes. Complexes of Human Papillomavirus 16 E6 Proteins Form Pseudo-DISC Structures During TNF-Medicated Apoptosis. J. Virol. 83:210-227, 2009. PMID: 18842714
- Tungteakkhun, S., M. Filippova, J. W. Neidigh, N. Fodor and P. J. Duerksen-Hughes. The Interaction Between HPV 16 E6 and FADD is Mediated by a Novel E6 Binding Domain. J. Virol. 82:9600-9614, 2008. PMID: 18632871
- Filippov, V., E. L. Schmidt, M. Filippova and P. J. Duerksen-Hughes. Splicing and splice factor SRp55 participate in the response to DNA damage by changing isoform ratios of target genes. Gene. 420:34-41, 2008. PMID: 18571879
- Filippov, V., M. Filippova and P. J. Duerksen-Hughes. The Early Response to DNA Damage Can Lead to Activation of Alternative Splicing Activity Resulting in CD44 Splice Pattern Changes. Cancer Research. 67:7621-7630, 2007. PMID: 17699766
- Garrett, T. O., M. Filippova and P. J. Duerksen-Hughes. Bid is Cleaved Upstream of Caspase-8 Activation During TRAIL-Mediated Apoptosis in Human Osteosarcoma Cells. Apoptosis. 12:1299-1315, 2007. PMID: 17431792
- Filippova, M., M. M. Johnson, M. Bautista, V. Filippov, N. Fodor, S. S. Tungteakkhun, K. Williams and P. J. Duerksen-Hughes. The Large and Small Isoforms of HPV 16 E6 Bind to and Differentially Affect Procaspase 8 Stability and Activity. J. Virology. 81:4116-4129, 2007. PMID: 17267478
- Garnett T. O., M. Filippova and P. J. Duerksen-Hughes. Accelerated degradation of FADD and procaspase 8 in cells expressing human papillomavirus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death and Differentiation 13:1915-1926, 2006. PMID: 16528366
- Filippova, M., T. A. Brown-Bryan, C. A. Casiano and P. J. Duerksen-Hughes. The human papillomavirus 16 E6 can render cells either sensitive or resistant to TNF: Effect of dose. Cell Death and Differentiation 12:1622-1635, 2005. PMID: 15933739
- Filippova, M., Parkhurst, L. and P. J. Duerksen-Hughes. HPV 16 E6 Binds to FADD and Modulates Fas-Triggered Apoptosis. J. Biol. Chem. 279:25729-25744, 2004. PMID: 15073179
- Filippova, M., H. Song, J. L. Connolly, T. S. Dermody, and P. J. Duerksen-Hughes. The human papillomavirus 16 E6 protein binds to TNF R1 and protects cells from TNF-triggered apoptosis. J. Biol. Chem. 277:21730-21739, 2002. PMID: 11934887
- Yang, J. and P. J. Duerksen-Hughes. Activation of a p53 -independent, sphingolipid-mediated cytolytic pathway in p53-negative mouse fibroblast cells treated with N-methyl-N-nitro-N-nitrosoguanidine. J. Biol. Chem. 276:27129-27135, 2001. PMID: 11369765