PMID- 36116741
OWN - NLM
STAT- MEDLINE
DCOM- 20221019
LR  - 20221222
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 550
DP  - 2022 Dec 1
TI  - PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune 
      responses via the cGAS signaling pathway in colorectal cancer.
PG  - 215919
LID - S0304-3835(22)00406-2 [pii]
LID - 10.1016/j.canlet.2022.215919 [doi]
AB  - In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and 
      regulate DNA repair pathways to protect against DNA damage and cell death caused 
      by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have 
      been combined in clinical trials, but their action mechanisms remain unclear. 
      Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic 
      GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically 
      ferroptosis, via the activating transcription factor 3 (ATF3)-solute carrier 
      family 7 member 11 axis and the antitumor immune response via the 
      interferon-beta-CD8(+) T cell pathway. Niraparib, a widely used PARPi, augmented 
      cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, 
      cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 
      (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced 
      infiltration of CD8(+) T or CD8(+)GZMB(+) T cells in the cGAS KD group. Survival 
      analysis of paired tumor samples before and after standard radiotherapy revealed 
      that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8(+) T 
      cells resulted in a significantly high disease-free survival rate in patients 
      with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic 
      accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor 
      control in cancer cell lines and mouse xenograft models.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Shen, Dongya
AU  - Shen D
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Luo, Jia
AU  - Luo J
AD  - Department of Hepatobiliary and Intestinal Surgery, Hunan Cancer Hospital, 
      Changsha, Hunan, China.
FAU - Chen, Ling
AU  - Chen L
AD  - Department of Gastrointestinal Surgery, Xiangya Hospital, Central South 
      University, Changsha, Hunan, China.
FAU - Ma, Wenjuan
AU  - Ma W
AD  - Department of Anesthesiology, Xiangya Hospital, Central South University, China.
FAU - Mao, Xiaoyuan
AU  - Mao X
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Zheng, Juyan
AU  - Zheng J
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Wang, Yang
AU  - Wang Y
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Wan, Jielin
AU  - Wan J
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Wang, Shiyu
AU  - Wang S
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Ouyang, Jing
AU  - Ouyang J
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Yi, Hanying
AU  - Yi H
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Liu, Dongbo
AU  - Liu D
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Huang, Weihua
AU  - Huang W
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China; The First Affiliated Hospital of Guangdong Pharmaceutical 
      University, Guangzhou, 510060, China.
FAU - Liu, Zhaoqian
AU  - Liu Z
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China.
FAU - McLeod, Howard L
AU  - McLeod HL
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; Intermountain Precision Genomics, Intermountain Healthcare, St. George, 
      UT, 84770, USA. Electronic address: hmcleod1965@gmail.com.
FAU - He, Yijing
AU  - He Y
AD  - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      China; National Clinical Research Center for Geriatric Disorders, Xiangya 
      Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, China; Engineering Research Center 
      of Applied Technology of Pharmacogenomics, Ministry of Education, Central South 
      University, China. Electronic address: heyijing@csu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220916
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Activating Transcription Factor 3)
RN  - 0 (Membrane Proteins)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 681HV46001 (Ribose)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.7.- (Nucleotidyltransferases)
SB  - IM
MH  - Activating Transcription Factor 3
MH  - Adenosine Diphosphate/metabolism/pharmacology
MH  - Animals
MH  - CD8-Positive T-Lymphocytes
MH  - *Colorectal Neoplasms/drug therapy/radiotherapy
MH  - Cyclooxygenase 2/metabolism
MH  - *Ferroptosis
MH  - Humans
MH  - Immunity
MH  - Interferon-beta/pharmacology
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Nucleotidyltransferases/genetics/metabolism
MH  - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
MH  - Ribose/metabolism/pharmacology
MH  - Signal Transduction
OTO - NOTNLM
OT  - Activating transcription factor 3
OT  - CD8(+) T cell
OT  - Ionizing radiation
OT  - Niraparib
OT  - cGAS pathway
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/09/19 06:00
MHDA- 2022/10/20 06:00
CRDT- 2022/09/18 19:27
PHST- 2022/05/25 00:00 [received]
PHST- 2022/09/01 00:00 [revised]
PHST- 2022/09/11 00:00 [accepted]
PHST- 2022/09/19 06:00 [pubmed]
PHST- 2022/10/20 06:00 [medline]
PHST- 2022/09/18 19:27 [entrez]
AID - S0304-3835(22)00406-2 [pii]
AID - 10.1016/j.canlet.2022.215919 [doi]
PST - ppublish
SO  - Cancer Lett. 2022 Dec 1;550:215919. doi: 10.1016/j.canlet.2022.215919. Epub 2022 
      Sep 16.