Accumulating evidence suggests that the root of drug chemoresistance in
breast cancer is tightly associated with subpopulations of cancer stem cells (CSCs), whose activation is largely dependent on
taxol-promoting autophagy. Our pilot study identified
GRP78 as a specific marker for chemoresistance potential of breast CSCs by regulating Wnt/β-
catenin signaling. Ai Du Qing (ADQ) is a
traditional Chinese medicine formula that has been utilized in the treatment
cancer, particularly during the consolidation phase. In the present study, we investigated the regulatory effects and molecular mechanisms of ADQ in promoting autophagy-related
breast cancer chemosensitivity. ADQ with
taxol decreasing the cell proliferation and colony formation of
breast cancer cells, which was accompanied by suppressed breast CSC ratio, limited self-renewal capability, as well as attenuated multi-differentiation. Furthermore, autophagy in ADQ-treated breast CSCs was blocked by
taxol via regulation of β-
catenin/ABCG2 signaling. We also validated that autophagy suppression and chemosensitizing activity of this formula was GRP78-dependent. In addition,
GRP78 overexpression promoted autophagy-inducing chemoresistance in
breast cancer cells by stabilizing β-
catenin, while ADQ treatment downregulated
GRP78, activated the Akt/GSK3β-mediated
proteasome degradation of β-
catenin via ubiquitination activation, and consequently attenuated the chemoresistance-promoted effect of
GRP78. In addition, both mouse
breast cancer xenograft and zebrafish
xenotransplantation models demonstrated that ADQ inhibited mammary
tumor growth, and the breast CSC subpopulation showed obscure adverse effects. Collectively, this study not only reveals the chemosensitizating mechanism of ADQ in breast CSCs, but also highlights the importance of
GRP78 in mediating autophagy-promoting drug resistance via β-
catenin/ABCG2 signaling.