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

  • Cell Death Dis. 2022 Feb 21;13(2):166. doi: 10.1038/s41419-022-04611-4.
Hao Liu   #  1  2 ,  Dong Zhao   #  2 ,  Huayi Li  2 ,  Wenxin Zhang  2 ,  Qingyu Lin  2 ,  Xingwen Wang  2 ,  Shanliang Zheng  2 ,  Lei Zhang  3 ,  Li Li  4 ,  Shaoshan Hu  5 ,  Ying Hu  6
Affiliations
  • 1. Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital, Affiliated to Hangzhou Medical College, 310000, Hangzhou, Zhejiang, China.
  • 2. School of Life Science and Technology, Harbin Institute of Technology, 150001, Harbin, Heilongjiang Province, China.
  • 3. The Third Affiliated Hospital of Harbin Medical University, 150040, Harbin, Heilongjiang Province, China.
  • 4. Department of Pathology, Harbin Medical University, 150086, Harbin, Heilongjiang Province, China.
  • 5. Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital, Affiliated to Hangzhou Medical College, 310000, Hangzhou, Zhejiang, China. [email protected].
  • 6. School of Life Science and Technology, Harbin Institute of Technology, 150001, Harbin, Heilongjiang Province, China. [email protected].
  • # Contributed equally.
PMID: 35190529 DOI: 10.1038/s41419-022-04611-4
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.

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