PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis

doi:10.7150/jca.61622

	PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis
	Zheng, Xiaogang 1,2,3,4; Liu, Bingtao 1,2,3,4; Liu, Xiongxiong 1,2,3,4; Li, Ping 1,2,3,4; Zhang, Pengcheng 1,2,3,4; Ye, Fei 1,2,3,4; Zhao, Ting 1,2,3,4; Kuang, Yanbei 1,2,3,4; Chen, Weiqiang 1,2,3,4; Jin, Xiaodong 1,2,3,4
刊名	JOURNAL OF CANCER
	2022
卷号	13 期号:2 页码:669-680
关键词	PERK carbon ion ER stress autophagy ferroptosis
ISSN号	1837-9664
DOI	10.7150/jca.61622
通讯作者	Jin, Xiaodong(jinxd@impcas.ac.cn) ; Li, Qiang(liqiang@impcas.ac.cn)
英文摘要	PERK is one of the transmembrane sensors of unfolded protein response (UPR) triggered by ER stress. In this study, we evaluated the role of PERK in the sensitivity of hepatocellular carcinoma (HCC) cells to high linear energy transfer (LET) carbon ions (CI). We found that CI irradiation could induce ER stress in HCC cells. On the one hand, PERK promoted autophagy via regulating ATF4 expression; on the other hand, PERK regulated p53 expression, and the latter either induced autophagy through up-regulating DRAM, or directly promoting apoptosis through the mitochondrial pathway or facilitating ferroptosis via down-regulating SLC7AII (the extrinsic pathway), but independent of GPX4 (the intrinsic pathway). These factors jointly determined the sensitivity of HCC cells to high-LET CI radiation. Inhibiting TPS3 directly increased cellular radioresistance definitely. Moreover, the death of HepG2 (TPS3 wild type) cells induced by high-LET CI irradiation combined with sorafenib treatment might be caused by a mixed-type regulated cell death (RCD) including both apoptosis and ferroptosis, suggesting that apoptosis and ferroptosis are synergetic cell death modes regulated by TPS3, which is one of the reasons why the sensitivity of HepG2 cells is higher than that of Hep3B (TPS3 null type) and PLC/PRF5 (TPS3 mutated type) cells. Therefore, our work might shed light on the potential therapeutic implication of CI radiotherapy combined with PERK targeted clinical drugs to implement personalized and precise treatment of HCCs.
资助项目	National Natural Science Foundation of China[12005268] ; National Natural Science Foundation of China[11875299] ; National Natural Science Foundation of China[11705245] ; National Key Research and Development Program of China[2018YFC0115702] ; Key Deployment Project of the Chinese Academy of Sciences[KFZD-SW-222] ; Western Talents Program of the Chinese Academy of Sciences[99] ; Natural Science Foundation of Gansu Province[20JR5RA549] ; Foundation of the Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations[lzujbky-2021-kb05]
WOS关键词	UNFOLDED PROTEIN RESPONSE ; ENDOPLASMIC-RETICULUM STRESS ; CHARGED-PARTICLE THERAPY ; ER STRESS ; PATHWAY ; CANCER ; RADIOSENSITIZATION ; RADIORESISTANCE ; RADIOTHERAPY ; MECHANISM
WOS研究方向	Oncology
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000740062000025
资助机构	National Natural Science Foundation of China ; National Key Research and Development Program of China ; Key Deployment Project of the Chinese Academy of Sciences ; Western Talents Program of the Chinese Academy of Sciences ; Natural Science Foundation of Gansu Province ; Foundation of the Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/142449]
专题	中国科学院近代物理研究所
通讯作者	Jin, Xiaodong; Li, Qiang
作者单位	1.Chinese Acad Sci, Inst Modern Phys, 509 Nanchang Rd, Lanzhou 730000, Gansu, Peoples R China 2.Chinese Acad Sci, Key Lab Heavy Ion Radiat Biol & Med, Lanzhou 730000, Peoples R China 3.Key Lab Basic Res Heavy Ion Radiat Applicat Med, Lanzhou 730000, Gansu, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zheng, Xiaogang,Liu, Bingtao,Liu, Xiongxiong,et al. PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis[J]. JOURNAL OF CANCER,2022,13(2):669-680.
APA	Zheng, Xiaogang.,Liu, Bingtao.,Liu, Xiongxiong.,Li, Ping.,Zhang, Pengcheng.,...&Li, Qiang.(2022).PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis.JOURNAL OF CANCER,13(2),669-680.
MLA	Zheng, Xiaogang,et al."PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis".JOURNAL OF CANCER 13.2(2022):669-680.