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Tumor resistance to radiotherapy is triggered by an ATM/TAK1-dependent-increased expression of the cellular prion protein

Abstract

In solid cancers, high expression of the cellular prion protein (PrPC) is associated with stemness, invasiveness, and resistance to chemotherapy, but the role of PrPC in tumor response to radiotherapy is unknown. Here, we show that, in neuroblastoma, breast, and colorectal cancer cell lines, PrPC expression is increased after ionizing radiation (IR) and that PrPC deficiency increases radiation sensitivity and decreases radiation-induced radioresistance in tumor cells. In neuroblastoma cells, IR activates ATM that triggers TAK1-dependent phosphorylation of JNK and subsequent activation of the AP-1 transcription factor that ultimately increases PRNP promoter transcriptional activity through an AP-1 binding site in the PRNP promoter. Importantly, we show that this ATM-TAK1-PrPC pathway mediated radioresistance is activated in all tumor cell lines studied and that pharmacological inhibition of TAK1 activity recapitulates the effects of PrPC deficiency. Altogether, these results unveil how tumor cells activate PRNP to acquire resistance to radiotherapy and might have implications for therapeutic targeting of solid tumors radioresistance.

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Fig. 1: PRNP mRNA level increases after radiation exposure and PrPC deficiency decreases radioresistance in human tumor cells.
Fig. 2: An AP-1 binding site in the PRNP promoter is necessary to mediate PRNP gene activation after irradiation.
Fig. 3: Upregulation of PRNP triggered by irradiation depends on an ATM-JNK-c-Jun axis.
Fig. 4: Radiation-induced PRNP upregulation depends on an ATM-TAK1-JNK axis.

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Acknowledgements

The authors thank Guillaume Pitton for lentiviruses productions; Nathalie Déchamps for flow cytometric cell sorting, at the IRCM Flow Cytometry Shared Resource (established by equipment grants from DIM-Stem-Pôle, INSERM, Foundation ARC, and CEA); Marilene Lopes (Lab of Neurobiology and Stem Cells, Sao-Paulo, Brazil) for kindly providing the plasmid used for generating SH-SY5Y CRISPR KO cells; Sophie Mouillet-Richard, François Leteurtre and Jérôme Lebeau for providing colorectal, and breast cancer cell lines.This work was supported by the French National Electricity Company (EDF), the Transverse Division N°4 (Segment n°4 Radiobiology headed by Christophe Carles) and the Radiobiology Program (PRIONRAD) of the French Alternative Energies and Atomic Energy Commission (CEA).

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Correspondence to Jacqueline Bernardino-Sgherri or Anne Bravard.

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Bernardino-Sgherri, J., Siberchicot, C., Auvré, F. et al. Tumor resistance to radiotherapy is triggered by an ATM/TAK1-dependent-increased expression of the cellular prion protein. Oncogene 40, 3460–3469 (2021). https://doi.org/10.1038/s41388-021-01746-0

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