Interleukin-33 (IL-33) promotes DNA damage-resistance in lung cancer
Haoge Luo1, Liping Liu1, Xiaoping Liu2
1Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Abstract:
Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells.
Insights
Interleukin-33 (IL-33) from cancer cells and fibroblasts promotes tumor resistance to chemotherapy by enhancing DNA repair. Targeting IL-33 may overcome chemoresistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor cells resist chemotherapy and radiotherapy by repairing DNA damage.
- The tumor microenvironment (TME) influences DNA damage response.
- Interleukin-33 (IL-33) is implicated in promoting tumor therapeutic resistance.
Purpose of the Study:
- To investigate the source of IL-33 during cancer therapy.
- To elucidate the mechanisms by which IL-33 contributes to a resistant TME.
- To explore IL-33 as a potential therapeutic target for chemoresistant cancers.
Main Methods:
- Quantification of IL-33 expression in cancer-associated fibroblasts (CAFs) and tumor cells post-DNA damage induction.
- Analysis of IL-33's role in DNA damage repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ).
- Investigation of the IL-33/ST2 signaling axis in mediating therapeutic resistance.
Main Results:
- Both CAFs and tumor cells treated with DNA-damaging agents secrete high levels of IL-33.
- IL-33 enhances DNA damage repair efficacy, promoting tumor cell survival.
- Nuclear IL-33 acts as a transcriptional co-activator for HRR genes, while active IL-33 promotes NHEJ via the IL-33/ST2 pathway.
Conclusions:
- IL-33 is a key mediator of DNA damage resistance within the TME.
- IL-33 produced by CAFs and tumor cells contributes to therapeutic resistance.
- Targeting IL-33 represents a potential strategy to overcome chemoresistance in cancer.
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