Histone deacetylase inhibitor-induced sensitization to TNFα/TRAIL- mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression

Katalin Darvas, Simone Rosenberger, Dirk Brenner, Cornelius Fritsch, Nadine Gmelin, Peter H. Krammer, Frank Rösl*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

Histone-deacetylase (HDAC) inhibitors (HDACi) can block proliferation and induce intrinsic apoptosis in human papillomavirus (HPV)-positive cervical carcinoma cells, independently of copy number and integration locus of the viral DNA. Using HPV18-positive HeLa cells as model systems, we provide evidence that HDAC inhibition leads to transcriptional suppression of c-FLIP, which negatively regulates extrinsic apoptosis by preventing the recruitment of caspase-8 to the death-inducing signaling complex. Consequently, HDACi pretreatment renders cervical cancer cells sensitive to TNFα and TRAIL-induced apoptosis. Already 5-hr incubation with TNFα or TRAIL was sufficient to eradicate more than 40% of pretreated cells, which are normally completely refractory against respective death-ligands alone even under long-term incubation. Ectopic expression of either short or long splicing variant of c-FLIP, c-FLIPs and c-FLIPL, abrogates sensitization. Notably, combined HDACi/death ligand treatment did not result in eradication of HPV-negative cells, despite the fact that both c-FLIP isoforms were also downregulated. However, knocking down HPV18 E6/E7 transcription by siRNA prevents HDACi/death-ligand mediated apoptosis, indicating that continued viral oncogene expression favors sensitization. Here, the viral oncoprotein E7 seems to play a functional role, since only HPV16 E7-immortalized human keratinocytes underwent significant apoptosis on HDACi/TNFα treatment, whereas keratinocytes expressing only HPV16 E6 or primary keratinocytes were refractory under the same experimental conditions. Taken together, HDACi can be considered as an alternative therapeutic option in the treatment of premalignant and malignant lesions.

Original languageEnglish
Pages (from-to)1384-1392
Number of pages9
JournalInternational Journal of Cancer
Volume127
Issue number6
DOIs
Publication statusPublished - 1 Sep 2010
Externally publishedYes

Keywords

  • Cervical cancer
  • E6/E7 viral oncoproteins
  • Human papillomaviruses
  • Therapy
  • c-Flip isoforms

Fingerprint

Dive into the research topics of 'Histone deacetylase inhibitor-induced sensitization to TNFα/TRAIL- mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression'. Together they form a unique fingerprint.

Cite this