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PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune responses via the cGAS signaling pathway in colorectal cancer.
Shen, Dongya; Luo, Jia; Chen, Ling; Ma, Wenjuan; Mao, Xiaoyuan; Zhang, Yu; Zheng, Juyan; Wang, Yang; Wan, Jielin; Wang, Shiyu; Ouyang, Jing; Yi, Hanying; Liu, Dongbo; Huang, Weihua; Zhang, Wei; Liu, Zhaoqian; McLeod, Howard L; He, Yijing.
Afiliação
  • Shen D; 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; Engineerin
  • Luo J; Department of Hepatobiliary and Intestinal Surgery, Hunan Cancer Hospital, Changsha, Hunan, China.
  • Chen L; Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • Ma W; Department of Anesthesiology, Xiangya Hospital, Central South University, China.
  • Mao X; 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; Engineerin
  • Zhang Y; 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; Engineerin
  • Zheng J; 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; Engineerin
  • Wang Y; 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; Engineerin
  • Wan J; 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; Engineerin
  • Wang S; 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; Engineerin
  • Ouyang J; 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; Engineerin
  • Yi H; 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; Engineerin
  • Liu D; 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; Engineerin
  • Huang W; 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; Engineerin
  • Zhang W; 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; Engineerin
  • Liu Z; 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; Engineerin
  • McLeod HL; 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.
  • He Y; 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; Engineerin
Cancer Lett ; 550: 215919, 2022 Dec 01.
Article em En | MEDLINE | ID: mdl-36116741
ABSTRACT
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-ß-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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Ferroptose Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Ferroptose Idioma: En Ano de publicação: 2022 Tipo de documento: Article