Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2
Hao Liu1,2, Dong Zhao2, Huayi Li2
1Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital, Affiliated to Hangzhou Medical College, 310000, Hangzhou, Zhejiang, China.
Abstract:
The complex interaction between cancer cells and the immune microenvironment is a central regulator of tumor growth and the treatment response. Chemotherapy-induced senescence is accompanied by the senescence-associated secretion phenotype (SASP). However, the mechanisms underlying the regulation of the SASP remain the most poorly understood element of senescence. Here, we show that nuclear erythroid factor 2-like factor 2 (Nrf2), a master antioxidative transcription factor, accumulates upon doxorubicin-induced senescence. This is due to the increased cytoplasmic Inhibitor of Apoptosis Stimulating Protein of P53, iASPP, which binds with Keap1, interrupting Keap1/Nrf2 interaction and promoting Nrf2 stabilization and activation. Activated Nrf2 transactivates a novel target gene of SASP factor, macrophage colony-stimulating factor (M-CSF), which subsequently acts on macrophages and induces polarization from M1 to M2 via a paracrine mechanism. Genetic inhibition of iASPP-Nrf2 suppresses the growth of apoptosis-resistant xenografts, with further analysis revealing that M-CSF/M-CSFR-regulated macrophage polarization is critical for the functional outcomes delineated above. Overall, our data uncover a novel function of iASPP-Nrf2 in skewing the immune microenvironment under treatment-induced senescence. Targeting the iASPP-Nrf2 axis could be a powerful strategy for the implementation of new chemotherapy-based therapeutic opportunities.
Insights
Chemotherapy induces senescence, activating the iASPP-Nrf2 pathway. This pathway promotes M2 macrophage polarization via M-CSF, impacting tumor growth and treatment response. Targeting this axis offers new therapeutic strategies.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Senescence
Background:
- The tumor microenvironment and immune interactions critically influence cancer progression and treatment outcomes.
- Chemotherapy can induce cellular senescence, characterized by the senescence-associated secretion phenotype (SASP).
- Mechanisms regulating SASP remain poorly understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms of SASP following chemotherapy-induced senescence.
- To investigate the role of the nuclear erythroid factor 2-like factor 2 (Nrf2) pathway in senescence.
- To identify novel therapeutic targets within the senescence-immune microenvironment axis.
Main Methods:
- Doxorubicin treatment to induce senescence in cancer cells.
- Analysis of nuclear erythroid factor 2-like factor 2 (Nrf2) accumulation and its regulators.
- Investigation of the role of Inhibitor of Apoptosis Stimulating Protein of P53 (iASPP) in Nrf2 stabilization.
- Assessment of macrophage colony-stimulating factor (M-CSF) as a target gene of Nrf2.
- Evaluation of macrophage polarization (M1 to M2) induced by M-CSF.
- Genetic inhibition of the iASPP-Nrf2 axis in xenograft models.
Main Results:
- Doxorubicin-induced senescence leads to Nrf2 accumulation.
- Increased iASPP stabilizes Nrf2 by disrupting the Keap1/Nrf2 interaction.
- Activated Nrf2 upregulates M-CSF, a novel SASP factor.
- M-CSF induces paracrine M1 to M2 macrophage polarization.
- Genetic inhibition of iASPP-Nrf2 suppresses xenograft growth.
- M-CSF/M-CSFR signaling is crucial for these functional outcomes.
Conclusions:
- The iASPP-Nrf2 pathway plays a novel role in modulating the immune microenvironment during chemotherapy-induced senescence.
- Nrf2 activation by iASPP promotes M2 macrophage polarization through M-CSF.
- Targeting the iASPP-Nrf2 axis presents a promising strategy for enhancing chemotherapy efficacy.
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