Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines

Ryan J. Bourgo, Wesley A. Braden, Susanne I. Wells, Erik S. Knudsen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

High-risk human papilloma virus (HPV) encodes two oncoproteins, E6 and E7, which are vital to viral replication and contribute to the development of cervical cancer. HPV16 E7 can target over 20 cellular proteins, but is best known for inactivating the retinoblastoma (RB) tumor suppressor. RB functions by restraining cells from entering S-phase of the cell cycle, thus preventing aberrant proliferation. While it is well established that HPV16 E7 facilitates the degradation of the RB protein, the ability of the RB pathway to overcome E7 action is less well understood. In this study the RB-pathway was activated via the overexpression of the p16ink4a tumor suppressor or ectopic expression of an active allele of RB (PSM-RB). While p16ink4a had no influence on cell cycle progression, PSM-RB expression was sufficient to induce a cell cycle arrest in both SiHa and HeLa cells, HPV positive cervical cancer cell lines. Strikingly, this arrest led to the downregulation of E2F target gene expression, which was antagonized via enhanced HPV-E7 expression. Since downmodulation of E7 function is associated with chronic growth arrest and senescence, the effect of PSM-RB on proliferation and survival was evaluated. Surprisingly, sustained PSM-RB expression impeded the proliferation of SiHa cells, resulting in both cell cycle inhibition and cell death. From these studies we conclude that active RB expression can sensitize specific cervical cancer cells to cell cycle inhibition and cell death. Thus, targeted therapies involving activation of RB function may be effective in inducing cell death in cervical cancer.

Original languageEnglish (US)
Pages (from-to)45-55
Number of pages11
JournalMolecular Carcinogenesis
Volume48
Issue number1
DOIs
StatePublished - Jan 2009

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Retinoblastoma
Uterine Cervical Neoplasms
Cell Cycle
Cell Death
Cell Line
Papillomaviridae
Neoplasms
Retinoblastoma Protein
Oncogene Proteins
Cell Cycle Checkpoints
S Phase
HeLa Cells
Down-Regulation
Alleles
Cell Proliferation
Gene Expression

Keywords

  • Apoptosis
  • Cervical cancer
  • E7
  • HPV
  • RB

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines. / Bourgo, Ryan J.; Braden, Wesley A.; Wells, Susanne I.; Knudsen, Erik S.

In: Molecular Carcinogenesis, Vol. 48, No. 1, 01.2009, p. 45-55.

Research output: Contribution to journalArticle

Bourgo, Ryan J. ; Braden, Wesley A. ; Wells, Susanne I. ; Knudsen, Erik S. / Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines. In: Molecular Carcinogenesis. 2009 ; Vol. 48, No. 1. pp. 45-55.
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