A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells

Roger A. Vertrees, Gokul C. Das, Angela M. Coscio, Jingwu Xie, Joseph B. Zwischenberger, Paul J. Boor

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23 Scopus citations

Abstract

Lung cancer, the leading cause of cancer-related deaths in both men and women, is the consequence of disordered apoptosis, induction of which may have therapeutic utility. Hyperthermia has been identified as a stimulus for apoptosis. We investigated the mechanism of hyperthermia-induced cell death in ras-transformed lung cells. Effect of hyperthermia (43°C for 180 min) was compared between two cell lines, an immortalized (sv-40) normal human bronchial epithelial (BEAS2-B) and its malignant transformed (H-ras transfected) counterpart (BZR-T33). Survival after hyperthermia: 7-d growth culture BEAS2-B, 1.03 ± 0.007 and BZR-T33, 0.39 ± 0.008 (P < 0.05); clonogenic assays BEAS2-B, 0.76 ± 0.003 and BZR-T33, 0.41 ± 0.004 (P < 0.05). Hoechst positive (apoptotic) cells: BEAS2-B, 11 ± 3% and BZR-T33, 78 ± 5% (P < 0.05). TUNEL, DNA fragmentation, and Annexin-V all corroborate this result. Western blot comparing the effect of hyperthermia in BZR-T33 cells to BEAS2-B cells revealed: TRAIL and FAS-L displayed significant increases (threefold and twofold, respectively); caspase-3 showed a decrease in uncleaved form and an increase in cleaved form, and a 50-fold increase in activity effectively blocked with the caspase-3 inhibitor DEVD-fmk; caspase-9 showed near depletion of uncleaved; poly (ADP-ribose) polymerase (PARP) degradation was clearly visible during heating. After hyperthermia, gene expression demonstrates a 5.7-fold increase in TRAIL and insignificant changes in tumor necrosis factor-α (TNF-α), FAS-L, and caspases 3, 8, 9 in transformed cells. Data demonstrated that hyperthermia induces apoptosis in transformed cells, and that apoptosis is mediated by caspase-3 as a result of activation of cell-death membrane receptors of the tumor-necrosis-factor family. In summary, these data suggest that hyperthermia could become an additional modality in the multidisciplinary approach to the treatment of lung cancer.

Original languageEnglish (US)
Pages (from-to)111-121
Number of pages11
JournalMolecular Carcinogenesis
Volume44
Issue number2
DOIs
StatePublished - Oct 1 2005

Keywords

  • Apoptosis
  • Hyperthermia
  • Lung cancer
  • Ras
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Vertrees, R. A., Das, G. C., Coscio, A. M., Xie, J., Zwischenberger, J. B., & Boor, P. J. (2005). A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells. Molecular Carcinogenesis, 44(2), 111-121. https://doi.org/10.1002/mc.20124