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Park S, Auyeung A, Lee DL, et al. HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins. Cancers (Basel). 2021;13(5)doi: 10.3390/cancers13050949.
Park, S., Auyeung, A., Lee, D. L., Lambert, P. F., Carchman, E. H., & Sherer, N. M. (2021). HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins. Cancers, 13(5), . https://doi.org/10.3390/cancers13050949
Park, Soyeong, et al. "HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins." Cancers vol. 13,5 (2021). doi: https://doi.org/10.3390/cancers13050949
Park S, Auyeung A, Lee DL, Lambert PF, Carchman EH, Sherer NM. HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins. Cancers (Basel). 2021 Feb 24;13(5). doi: 10.3390/cancers13050949. PMID: 33668328; PMCID: PMC7956332.
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Cancers (Basel). 2021 Feb 24;13(5). doi: 10.3390/cancers13050949.

HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins.

Cancers

Soyeong Park, Andrew Auyeung, Denis L Lee, Paul F Lambert, Evie H Carchman, Nathan M Sherer

Affiliations

  1. McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
  2. Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA.
  3. Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
  4. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

PMID: 33668328 PMCID: PMC7956332 DOI: 10.3390/cancers13050949

Abstract

High-risk human papillomavirus strain 16 (HPV16) causes oral and anogenital cancers through the activities of two viral oncoproteins, E6 and E7, that dysregulate the host p53 and pRb tumor suppressor pathways, respectively. The maintenance of HPV16-positive cancers requires constitutive expression of E6 and E7. Therefore, inactivating these proteins could provide the basis for an anticancer therapy. Herein we demonstrate that a subset of aspartyl protease inhibitor drugs currently used to treat HIV/AIDS cause marked reductions in HPV16 E6 and E7 protein levels using two independent cell culture models: HPV16-transformed CaSki cervical cancer cells and NIKS16 organotypic raft cultures (a 3-D HPV16-positive model of epithelial pre-cancer). Treatment of CaSki cells with some (lopinavir, ritonavir, nelfinavir, and saquinavir) but not other (indinavir and atazanavir) protease inhibitors reduced E6 and E7 protein levels, correlating with increased p53 protein levels and decreased cell viability. Long-term (>7 day) treatment of HPV16-positive NIKS16 raft cultures with saquinavir caused epithelial atrophy with no discernible effects on HPV-negative rafts, demonstrating selectivity. Saquinavir also reduced HPV16's effects on markers of the cellular autophagy pathway in NIKS16 rafts, a hallmark of HPV-driven pre-cancers. Taken together, these data suggest HIV-1 protease inhibitors be studied further in the context of treating or preventing HPV16-positive cancers.

Keywords: E6; E7; HPV; cervical cancer; protease inhibitors

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