Autophagy-dependent sensitization effects of PARP inhibitors on recurrent nasopharyngeal carcinoma treated with carbon ion and photon irradiationOA
Tumor radioresistance and severe toxicity make reirradiation for recurrent nasopharyngeal carcinoma(NPC)a significant clinical challenge.This study aims to investigate the ability of the poly(ADP-ribose)polymerase(PARP)inhibitor olaparib to sensitize recurrent NPC cells irradiated with photon or carbon ion(C-ion),and to explore the underlying mechanism of the synergistic promotion of cell death by olaparib and ionizing radiation.The results show that olaparib has significant X-ray and C-ion radiosensitization effects on recurrent NPC cells and the associated HK-RR photon-resistant model.Radiation,particularly C-ion exposure,induces a homologous recombination(HR)-deficient gene signature in HR-proficient NPC cells,potentially increasing their sensitivity to PARP inhibition.C-ion and X-ray irradiation induces similar modes of cell death,and multiple cell death pathways[including apoptosis,necrosis,ferroptosis,senescence,and autophagic cell death(ACD)]contribute to the cytotoxic effects of radiation combined with olaparib,with AcD being the dominant pathway.Both the pharmacological and genetic inhibition of autophagy significantly attenuate the radiosensitization effect of olaparib.In conclusion,olaparib effectively sensitizes recurrent NPC cells to both X-ray irradiation and C-ion irradiation,with autophagy playing a central role in mediating this effect.
Ziyu Le;Haojiong Zhang;Li Chen;Wanzun Lin;Qingting Huang;Shikai Geng;Wei Hu;Huaiyuan Chen;Fangzhu Wan;Xingyu Liu;Jiyi Hu;Fengtao Su;Jiade JLu;Lin Kong
Department of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,ChinaShanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Cancer Institute,Fudan University Shanghai Cancer Center,Shanghai Medical College of Fudan University,Shanghai,ChinaDepartment of Radiation Oncology,Proton and Heavy lon Center,Heyou Hospital,Foshan 523000,ChinaDepartment of Radiation Oncology,Shanghai Proton and Heavy lon Center,Fudan University Cancer Hospital,Shanghai 201315,China Shanghai Key Laboratory of Radiation Oncology,Shanghai 201321,China Shanghai Engineering Research Center of Proton and Heavy lon Radiation Therapy,Shanghai 201321,China
医药卫生
recurrent nasopharyngeal carcinomaPARP inhibitorradiosensitivitycell deathautophagy
《Acta Biochimica et Biophysica Sinica》 2026 (3)
P.595-609,15
supported by the grants from the Natural Science Foundation of China(No.82103059)the Science and Technology Development Fund of Shanghai Pudong New Area(No.PKJ2021-Y45).
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