Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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IFI16 Enhances Chemosensitivity of Breast Cancer Cells by Inhibiting DNA Damage Response

  • Na-Lee Ka (College of Pharmacy, Chonnam National University) ;
  • Ga Young Lim (College of Pharmacy and Natural Products Research Institute, Seoul National University) ;
  • Seung‑Su Kim (College of Pharmacy and Natural Products Research Institute, Seoul National University) ;
  • Mi-Ock Lee (College of Pharmacy and Natural Products Research Institute, Seoul National University)
  • Received : 2025.05.06
  • Accepted : 2025.08.09
  • Published : 2025.11.01
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Abstract

Many chemotherapeutic agents exert their cytotoxic effects primarily by inducing DNA damage. In response to DNA damage, cells activate a signaling cascade known as DNA damage response (DDR) to repair the damage and promote cell survival. Accordingly, the capacity of the DDR in cancer cells is a critical factor that influences their sensitivity to chemotherapy. Here, we identified a role for interferon γ-inducible protein 16 (IFI16) in modulating the DDR and chemosensitivity of breast cancer cells. Depletion of IFI16 in MDA-MB-231 cells conferred resistance to the DNA-damaging agents doxorubicin and 5-fluorouracil, as evidenced by increased cell viability and reduced caspase-3 cleavage compared to control cells. Mechanistically, IFI16 interacted with the MRE11-RAD50-NBS1 complex and disrupted the interaction between NBS1 and ataxia telangiectasia mutated (ATM), a critical step for ATM activation. In vivo, xenograft tumors derived from IFI16 knockout cells exhibited diminished responses to doxorubicin treatment, characterized by decreased apoptotic cell death and reduced expression of DSB marker proteins, such as γH2AX and 53BP1. Furthermore, analysis of breast cancer patient datasets revealed that high IFI16 expression correlated with an improved pathological complete response rate following chemotherapy. Our findings suggest that IFI16 could serve as both a predictive biomarker for chemotherapy response and a potential therapeutic target for enhancing the efficacy of DNA-damaging agents.

Keywords

Acknowledgement

This project was supported by grants from the National Research Foundation of Korea (2022R1A2C2006318 and RS-2022-NR072454).

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