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.
Highlights
Systemic chemotherapy remains the primary treatment for cancer
We explored whether nuclear erythroid factor 2-like factor 2 (Nrf2) contributes to the effect of (Inhibitor of Apoptosis Stimulating Protein of P53) in the iASPP on cytokines that it positively regulates under both basal cytoplasm
In line with We investigate whether macrophage colony-stimulating factor (M-CSF) is a direct transcriptional target of previous reports, iASPP was found to be increased in a time- Nrf2
Summary
Systemic chemotherapy remains the primary treatment for cancer. Drug resistance is a major barrier that limits its effectiveness [1,2,3,4]. How chemotherapy- by antioxidant response element (ARE) reporter activity, was induced senescent tumor cells direct immune cells from an active increased in Dox-treated cells, while iASPP knockdown (KD) to suppressive state, benefiting tumor growth and promoting abolished Dox-induced ARE activity (Fig. 1G) These data are in drug resistance, remains unclear, as is whether oncogenes are agreement with our previously proposed model that iASPP involved in modulating this process by changing SASP profiling. Two independent si-iASPP oligos iASPP-Nrf is a promising target for the sensitization of drug suppressed iASPP expression (Fig. 2C), which subsequently responses by multiple mechanisms, in addition to well-established inhibited senescence-induced M-CSF mRNA expression in cancer cell-autonomous mechanisms. Binding between iASPP and Keap nt) mutant of the M-CSF promoter, but not those controlled by was detected under basal conditions and their interaction was other truncated mutants, responded to Nrf overexpression or KD
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