Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2 polarization.

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.

• Authors: Hao Liu, Dong Zhao, Huayi Li, Wenxin Zhang, Qingyu Lin, Xingwen Wang, Shanliang Zheng, Lei Zhang, Li Li, Shaoshan Hu, Ying Hu
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 2 Pg. 166 (02 21 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35190529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Macrophage Colony-Stimulating Factor

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Polarity
• Humans
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Macrophage Activation
• Macrophage Colony-Stimulating Factor (antagonists & inhibitors, metabolism)
• NF-E2-Related Factor 2 (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, pathology)
• Tumor Microenvironment