Attenuation of p53 signaling by CDK8/19 sensitizes tumor cells to ionizing radiation

Authors: Kuchur О.А., Alexander Zavirsky, Shtil A. A.

Responses of tumor cells to therapeutic ionizing radiation include a number of processes largely mediated by the transcription factor p53. To explore the possibility of tumor cell radiosensitization by targeting p53 dependent mechanisms we investigated the role of transcriptional protein kinases CDK8/19 in the balance of cell death vs survival upon irradiation. Our results indicate that CDK8/19 inhibition in the irradiated wild type p53 cells is functionally similar to p53 KO: pharmacological attenuation of p53 responses (HCT116 cells) or genetic inactivation of p53 (HCT116p53KO cells) abrogate the G2/M checkpoint and preclude the repair of irradiation induced damage. Thus, inhibition of CDK8/19 mediated transcriptional reprogramming emerges as a therapeutically attractive approach in tumor radiosensitization.