DNA damage response in human testicular germ cell tumor cell lines treated with cisplatin

Abstract

Cisplatin-based chemotherapy is known to be exceptionally effective in the treatment of testicular germ cell tumors. The molecular mechanisms underlying the sensitivity of testicular germ cell tumor cell lines to cisplatin treatment seem to be multifactorial, possibly including a low capacity to remove cisplatin-DNA adducts by nucleotide excision repair (NER), and their proneness to die by apoptosis. In this study we investigated the DNA damage response in two testicular germ cell tumor cell lines. Despite reduced levels of several NER proteins in the testis cancer cell lines, a proficient removal of UVC-induced DNA lesions by NER was observed using an alkaline comet assay. Moreover, we studied the transcriptional targets in these cells in response to cisplatin, particularly the expression profiles of genes associated with DNA damage response. Data from microarray experiments revealed the differential expression of several DNA damage response genes. One such gene, ataxia telangiectasia mutated (ATM) plays an important role in DNA damage signaling. Further analyses showed a pronounced induction of ATM also at the protein level, and the phosphorylations of ATM and its downstream target, Chk2. These findings support the involvement of ATM signaling in response to cisplatin in the testis cancer cell lines. To our knowledge, a similar level of ATM activation in response to cisplatin does not seem to occur in cancer cells of somatic origin.