Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel une signalisation défaillante des voies de réponse aux atteintes à l'ADN induit une résistance à la chimiothérapie dans les carcinomes épidermoïdes de la cavité buccale
Activation of the cellular DNA damage response (DDR) is an important determinant of cell sensitivity to cisplatin and other chemotherapeutic drugs that eliminate tumor cells through induction of DNA damage. It is therefore important to investigate whether alterations of the DNA damage signaling pathway confer chemoresistance in cancer cells, and whether pharmacological manipulation of the DDR pathway can re-sensitize these cells to cancer therapy. In a panel of oral/laryngeal squamous cell carcinoma (SCC) cell lines, we observed deficiencies in DNA damage signaling in correlation with cisplatin-resistance, but not with DNA repair. These deficiencies are consistent with reduced expression of components of the ATM-dependent signaling pathway and, in particular, strong up-regulation of Wip1, a negative regulator of the ATM pathway. Wip1 knockdown or inhibition enhanced DNA damage signaling and re-sensitized oral SCC cells to cisplatin. In contrast to the previously reported involvement of Wip1 in cancer, Wip1 up-regulation and function in these SCC cells is independent of p53. Finally, using xenograft tumor models, we demonstrated that Wip1 up-regulation promotes tumorigenesis and its inhibition improves the tumor response to cisplatin. Thus, this study reveals that chemoresistance in oral SCCs is partially attributed to deficiencies in DNA damage signaling, and Wip1 is an effective drug target for enhanced cancer therapy.
http://mct.aacrjournals.org/content/early/2012/09/12/1535-7163.MCT-12-0448.abstract