DNA damage recognition via activated ATM and p53 pathway in nonproliferating human prostate tissue

Sari Jäämaa, Taija M. Af Hällström, Anna Sankila, Ville Rantanen, Hannu Koistinen, Ulf Håkan Stenman, Zhewei Zhang, Zhiming Yang, Angelo M. De Marzo, Kimmo Taari, Mirja Ruutu, Leif C. Andersson, Marikki Laiho

Research output: Contribution to journalArticlepeer-review

Abstract

DNA damage response (DDR) pathways have been extensively studied in cancer cell lines and mouse models, but little is known about how DNA damage is recognized by different cell types in nonmalignant, slowly replicating human tissues. Here, we assess, using ex vivo cultures of human prostate tissue, DDR caused by cytotoxic drugs (camptothecin, doxorubicin, etoposide, and cisplatin) and ionizing radiation (IR) in the context of normal tissue architecture. Using specific markers for basal and luminal epithelial cells, we determine and quantify cell compartment-specific damage recognition. IR, doxorubicin, and etoposide induced the phosphorylation of H2A.X on Ser139 (γH2AX) and DNA damage foci formation. Surprisingly, luminal epithelial cells lack the prominent γH2AX response after IR when compared with basal cells, although ATM phosphorylation on Ser1981 and 53BP1 foci were clearly detectable in both cell types. The attenuated γH2AX response seems to result from low levels of total H2A.X in the luminal cells. Marked increase in p53, a downstream target of the activated ATM pathway, was detected only in response to camptothecin and doxorubicin. These findings emphasize the diversity of pathways activated by DNA damage in slowly replicating tissues and reveal an unexpected deviation in the prostate luminal compartment that may be relevant in prostate tumorigenesis. Detailed mapping of tissue and cell type differences in DDR will provide an outlook of relevant responses to therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)8630-8641
Number of pages12
JournalCancer Research
Volume70
Issue number21
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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