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

• Published in: Cell death & disease Vol. 13; no. 2; p. 166
• Main Authors: Liu, Hao, Zhao, Dong, Li, Huayi, Zhang, Wenxin, Lin, Qingyu, Wang, Xingwen, Zheng, Shanliang, Zhang, Lei, Li, Li, Hu, Shaoshan, Hu, Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/89; 38/1; 42; 631/67/68; 631/80/509; 64; 64/60; 82; 82/51; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Polarity; Chemotherapy; Colony-stimulating factor; Doxorubicin; Humans; Immunology; Kelch-Like ECH-Associated Protein 1 - metabolism; Life Sciences; Macrophage Activation; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Macrophage Colony-Stimulating Factor - metabolism; Microenvironments; Neoplasms - drug therapy; Neoplasms - pathology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - metabolism; p53 Protein; Paracrine signalling; Phenotypes; Polarization; Senescence; Tumor Microenvironment; Tumors; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04611-4

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.