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Cytokeratin 18 Expression Inhibits Cytokine-Induced Death of Cervical Cancer Cells
  1. Brian T. Sullivan, MS*,,
  2. Jessica A. Cherry, MS,
  3. Hideo Sakamoto, PhD*,,
  4. Luiz E. Henkes, PhD*,,
  5. David H. Townson, PhD and
  6. Bo R. Rueda, PhD*,
  1. * Vincent Center for Reproductive Biology, MGH/Department of Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA;
  2. Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH; and
  3. Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA.
  1. Address correspondence and reprint requests to Bo R. Rueda, PhD, Vincent Center for Reproductive Biology, Massachusetts General Hospital, THR 901A, 55 Fruit St, Boston, MA 02114. E-mail: brueda{at}; or David H. Townson, PhD, University of New Hampshire, Department of Molecular, Cellular and Biomedical Sciences, 129 W Main St, Durham, NH 03824. E-mail: dave.townson{at}


Objectives: In cervical cancer, increased cytokeratin 18 (CK18) filament expression is associated with disease progression. However, it may also provide resistance to cytokine-induced apoptosis. The present study tested whether CK18 expression influences susceptibility to cytokine-induced apoptosis.

Methods: The cervical cancer cell lines C-4II (high CK18 expression), ME-180 (low CK18 expression), and 2 subtypes of HeLa cells containing or lacking CK18 expression (CK18+ and CK18 cells, respectively) were exposed to vehicle (control), Fas ligand (FasL) (50 ng/mL), or tumor necrosis factor α (TNF-α; 10 ng/mL) without/with cycloheximide (CHX; 2.5 μg/mL) to test the hypothesis that diminished CK18 expression increases susceptibility to cytokine-induced apoptosis.

Results: Flow cytometric analysis of cell death via TUNEL staining revealed that cytokine-induced apoptosis was 2-fold greater in ME-180 cells than C-4II cells in response to FasL+CHX or TNF-α+CHX (P < 0.05). Similarly, there was a higher incidence of FasL-induced apoptosis in CK18 HeLa cells (23% and 91% apoptotic for FasL and FasL+CHX, respectively) than CK18+ HeLa cells (1% and 11%, respectively; P < 0.05). Surprisingly, TNF-α had no effect on either CK18+ or CK18 HeLa cells (P > 0.05). Caspase 3 activity was greater in CK18 HeLa cells than in CK18+ HeLa cells at 8 and 18 hours after FasL treatment (P < 0.05), an effect abrogated by the caspase 8 inhibitor IETD-fmk (P < 0.05).

Conclusions: Cervical cancer cells with diminished CK18 expression are more susceptible to cytokine-induced apoptosis, particularly in response to FasL treatment. These observations suggest that relative CK18 expression is an important factor when considering therapeutic strategies to enhance immune cell-mediated death of cervical cancer cells.

  • Cervix
  • Apoptosis
  • Cytokeratin
  • Cytokines

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