Ionizing Radiation Combined with PARP1 Inhibitor Reduces Radioresistance in Prostate Cancer with RB1/TP53 Loss

Abstract

Tumor suppressor genes RB1 and TP53 are altered frequently in prostate cancer (PC), whether RB1 and TP53 inactivation promotes radioresistance remains unclear. Herein, we demonstrated that RB1 loss enhanced ionizing radiation (IR)-induced DNA damage to inhibit cell proliferation and promote cellular senescence through a TP53-dependent pathway in LNCaP cells. Furthermore, the stabilization of TP53 was regulated by ATM-mediated phosphorylation of MDM2 at Ser395. However, inactivation of RB1/TP53 reversed DNA damage-induced cellular senescence and promoted radiation survival. Importantly, combined with PARP1 inhibitor restored radiosensitivity. This finding provides a potential approach for the therapy of PC with RB1/TP53 inactivation.

Keywords:

• Prostate cancer
• RB1
• TP53
• radioresistance
• PARP1

Author contributions

Y.F and XH.W. conceived and designed this study. Y.F. and H.F. performed most of the experiments and analyzed the data except for DNA damage modeling, Immunofluorescence. Z.Q. provided guidance and advice. Y.F., H.F. and Q.Z. prepared the manuscript with input from all authors.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This study was supported by National Natural Science Foundation of China [81802543 to Z.Q].