Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells

Abstract

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro‐metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1‐enriched EVs from apoptotic TNBC cells (EV‐Apo). EV‐Apo promoted the chemoresistance and invasion of co‐cultured TNBC cells by polarizing M2 macrophages through activating PD‐L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co‐cultured TNBC cells to paclitaxel chemotherapy via modulating EV‐Apo signalling. Mechanistically, BHS remarkably decreased C‐X‐C motif chemokine ligand 1 (CXCL1) cargo within EV‐Apo and therefore attenuated macrophage M2 polarization by suppressing PD‐L1 activation. Additionally, BHS decreased EV‐Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31‐FLOT2 complex‐driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV‐ApoCXCL1‐induced PD‐L1 activation and M2 polarization of tumour‐associated macrophages (TAMs). This pioneering study sheds light on EV‐ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV‐ApoCXCL1 biogenesis.

Keywords

• chemotherapy
• dying cell signalling
• extracellular vesicles
• triple‐negative breast cancer
• tumour‐associated macrophage