Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models
Shuanglian Wang, … , Mien-Chie Hung, Junwei Hou
Shuanglian Wang, … , Mien-Chie Hung, Junwei Hou
Published October 26, 2023
Citation Information: J Clin Invest. 2024;134(1):e166841. https://doi.org/10.1172/JCI166841.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 1

Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models

  • Text
  • PDF
Abstract

Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8–mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell–derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.

Authors

Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou

×

Figure 1

GSDMC-mediated CCP enhances the cytotoxicity of PARPi.

Options: View larger image (or click on image) Download as PowerPoint
GSDMC-mediated CCP enhances the cytotoxicity of PARPi.
(A) Representativ...
(A) Representative IHC staining results for GSDMC in human TNBC tissues. Scale bar: 50 μm. (B) MDA-MB-436 and HCC1937 cells harboring an empty vector (vector) or expressing WT GSDMC (GSDMC-WT) or the D365A mutant (GSDMC-mut). Immunoblotting demonstrating caspase-8 cleavage of GSDMC in indicated cells treated with olaparib (20μM) for 48 hours. (C) Cells in B were treated with olaparib (20 μM) for 72 hours. Cell death measured by LDH release (LDH-released cell death) is shown (n = 3). (D) Same treatment as in C; representative images of dying cell morphology. Red arrows indicate cell swelling with large bubbles. Scale bar: 20 μm. (E) Cells in B were treated with the indicated concentrations of olaparib for 72 hours and subjected to a cell viability assay (n = 3). (F) MDA-MB-157 and Hs578t cells with deletion of GSDMC or caspase-8 were treated with olaparib (100 μM) for 72 hours. LDH-released cell death is shown (n = 3). (G) Cells in F were treated with the indicated concentrations of olaparib for 72 hours and subjected to a cell viability assay (n = 3). Data represent mean ± SD. 1-way ANOVA was used. **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 1 X users
12 readers on Mendeley
See more details