Targeting PERK-ATF4-P21 axis enhances the sensitivity of osteosarcoma HOS cells to Mppα-PDT

作者全名："Zhong, Shenxi; Zhang, Ye; Mou, Hai; Jian, Changchun; Huang, Qiu; Ou, Yunsheng"

作者地址："[Zhong, Shenxi; Zhang, Ye; Mou, Hai; Jian, Changchun; Huang, Qiu; Ou, Yunsheng] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China; [Zhong, Shenxi; Zhang, Ye; Mou, Hai; Jian, Changchun; Huang, Qiu; Ou, Yunsheng] Chongqing Med Univ, Orthoped Lab, Chongqing 400016, Peoples R China"

通信作者："Ou, YS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China.; Ou, YS (通讯作者)，Chongqing Med Univ, Orthoped Lab, Chongqing 400016, Peoples R China."

来源：AGING-US

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001163813000048

JCR分区：Q2

影响因子：5.2

年份：2024

卷号：16

期号：3

开始页：2789

结束页：2811

文献类型：Article

关键词：MPP alpha-PDT; human osteosarcoma; PERK pathway; autophagy; apoptosis; p21

摘要："Osteosarcoma (OS) is the most prevalent type of malignant bone tumor in adolescents. The overall survival of OS patients has reached a plateau recently. Thus, there is an urgent need to develop approaches to improve the sensitivity of OS to therapies. Pyropheophorbide-alpha methyl ester-mediated photodynamic therapy (MPP alpha-PDT) is a new type of tumor therapy, and elucidating its mechanism is helpful to improve its anti-tumor efficacy. Here, we investigated how PERK signaling promotes the human OS (HOS) cell survival induced by MPP alpha-PDT, as overcoming this may enhance sensitivity to MPP alpha-PDT. We found that MPP alpha-PDT combined with PERK inhibitor GSK2656157 enhanced HOS cell apoptosis by suppressing autophagy and p21. Autophagy inhibition and p21 depletion enhanced cell death, indicating pro-survival effects in MPP alpha-PDT. Notably, p21 was found to be an effector of the PERK-Atf4 pathway, which could positively regulate autophagy mediated by MPP alpha-PDT. In conclusion, we found that the combination of MPP alpha-PDT and GSK2656157 enhanced apoptosis in HOS cells by inhibiting autophagy. Mechanistically, this autophagy is p21-dependent and can be suppressed by GSK2656157, thereby enhancing sensitivity to MPP alpha-PDT."

基金机构："National Natural Science Foundation of China [82172682, 82373221]; Chongqing Science and Technology Commission [CSTB2023NSCQ-MSX0472]; The 2022 First-class Discipline Construction Project of the First Affiliated Hospital of Chongqing Medical University [CYYY-BSYJSCXXM-202207]; The 2023 First-class Discipline Construction Project of the First Affiliated Hospital of Chongqing Medical University [CYYY-BSYJSCXXM-202304]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 82172682, No. 82373221) ; Chongqing Science and Technology Commission (No. CSTB2023NSCQ-MSX0472) ; 2022 First-class Discipline Construction Project of the First Affiliated Hospital of Chongqing Medical University (No. CYYY-BSYJSCXXM-202207) ; 2023 First-class Discipline Construction Project of the First Affiliated Hospital of Chongqing Medical University (No. CYYY-BSYJSCXXM-202304) ."