DDX58 deficiency leads to doxorubicin chemotherapy resistance by hindering Type I IFN signalling-mediated apoptosis in TNBC

Abstract

Abstract Triple-negative breast cancer (TNBC) lacks therapeutic targets for precision treatment, making cytotoxic chemotherapy still the primary treatment, but drug resistance often occurs. Unveiling mechanisms for TNBC chemoresistance and trying to reverse this process would undoubtedly improve the overall outcomes. Through three GEO datasets, we found that DDX58 gene was associated with pathological Complete Response (pCR) in breast cancer patients after neoadjuvant therapy. DDX58 is also known as retinoic acid-inducible gene I (RIG-I), and then we verified that DDX58 with lower expression was associated with poor prognosis in TNBC. The knockdown and knockout (CRISPR/Cas9) of DDX58 could inhibit proliferation while promoting migration and invasion (P < 0.001) in TNBC cells. We further found that the DDX58-knockout (DDX58-KO) cells were resistant to doxorubicin (Dox) treatment in a dose-dependent manner. Mechanistically, we indicated that double-stranded RNAs (dsRNAs) and mitochondrial antiviral-signaling protein (MAVS) were significantly increased by Dox treatment, and then cell apoptosis was mediated by the activated RIG-I and the upstream Type I interferon (IFN) signalling pathway in TNBC. Therefore, the deficiency of DDX58 decreased Dox-induced apoptosis in TNBC cells. Finally, within the Dox treatment, we found that the deficiency of DDX58 inhibited tumour cells apoptosis, and the tumour growth inhibition rate (IR) of the DDX58-KO group (43%) was lower than that of the WT group (68%) in a xenograft BALB/c nude mouse model. Taken together, we demonstrated that DDX58 deficiency led to Dox chemoresistance of TNBC by inhibiting cell apoptosis in vivo and vitro. These results supply new insights into that DDX58 might increase the efficacy of Dox in TNBC, thus providing a promising therapeutic strategy for chemotherapy of TNBC.