Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells

Marc Mendonca, Kelly L. Howard, Daphne L. Farrington, Lael A. Desmond, Toni M. Temples, Brendan M. Mayhugh, John J. Pink, David A. Boothman

Research output: Contribution to journalArticle

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Abstract

HeLa X human skin fibroblast hybrid cells have been developed into a model for radiation-induced neoplastic transformation of human cells. Previous studies indicate that the appearance of neoplastically transformed loci in this system is delayed for several population doublings after irradiation and appears to involve the loss of putative tumor suppressor loci on fibroblast chromosomes 11 and 14. We now show that after treatment with 7 Gy of X-rays, transformed loci initiation correlates with delayed apoptosis initiated in the progeny of the irradiated cells after 10-12 cell divisions and with reduced plating efficiency (delayed death). The cells develop classic apoptotic morphology, positive terminal deoxynucleotidyl transferase- mediated nick end labeling and phosphatidylserine (annexin V) staining, and cleavage of poly(ADP-ribose) polymerase. In addition, a delayed induction of the p53 protein and the proapoptotic Bax protein is evident over a week after radiation exposure. We propose that a delayed build-up of mitosis-dependent genomic DNA damage or a loss of genetic material over time (10-12 cell divisions postirradiation) has two relevant outcomes: (a) cell death due to the delayed induction of a p53-dependent apoptosis; and (b) neoplastic transformation of a minor subset of survivors that has lost fibroblast chromosomes 11 and 14 (tumor suppressor loci for this system) and has either evaded apoptosis or not acquired enough genetic damage to induce apoptosis. It is postulated that both phenomena result from X-ray-induced, translesion- mediated genomic instability.

Original languageEnglish
Pages (from-to)3972-3979
Number of pages8
JournalCancer Research
Volume59
Issue number16
StatePublished - Aug 15 1999

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Hybrid Cells
Radiation
Apoptosis
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 11
Fibroblasts
Cell Division
Neoplastic Cell Transformation
X-Rays
bcl-2-Associated X Protein
DNA Nucleotidylexotransferase
Poly(ADP-ribose) Polymerases
Genomic Instability
Annexin A5
Phosphatidylserines
Mitosis
DNA Damage
Neoplasms
Cell Death
Staining and Labeling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mendonca, M., Howard, K. L., Farrington, D. L., Desmond, L. A., Temples, T. M., Mayhugh, B. M., ... Boothman, D. A. (1999). Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells. Cancer Research, 59(16), 3972-3979.

Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells. / Mendonca, Marc; Howard, Kelly L.; Farrington, Daphne L.; Desmond, Lael A.; Temples, Toni M.; Mayhugh, Brendan M.; Pink, John J.; Boothman, David A.

In: Cancer Research, Vol. 59, No. 16, 15.08.1999, p. 3972-3979.

Research output: Contribution to journalArticle

Mendonca, M, Howard, KL, Farrington, DL, Desmond, LA, Temples, TM, Mayhugh, BM, Pink, JJ & Boothman, DA 1999, 'Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells', Cancer Research, vol. 59, no. 16, pp. 3972-3979.
Mendonca M, Howard KL, Farrington DL, Desmond LA, Temples TM, Mayhugh BM et al. Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells. Cancer Research. 1999 Aug 15;59(16):3972-3979.
Mendonca, Marc ; Howard, Kelly L. ; Farrington, Daphne L. ; Desmond, Lael A. ; Temples, Toni M. ; Mayhugh, Brendan M. ; Pink, John J. ; Boothman, David A. / Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells. In: Cancer Research. 1999 ; Vol. 59, No. 16. pp. 3972-3979.
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