Abstract
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.
Highlights
Breast cancer remains the most common malignant cancer among women, and is the second most common cause of death in women, with 8.6 million new cases and 4.2 million related deaths in 2018 (Bray et al, 2018; Byrd et al, 2020; Shieh and Tice, 2020)
These results indicate that Ai Du Qing (ADQ) at non-cytotoxic doses effectively suppresses breast cancer cells, as well as enhances the chemosensitivity of breast cancer cells when administered in combination with taxol
Because breast cancer stem cells (CSCs) always exist in the form of spheres, i.e., non-adherent spherical clusters of cells, we examined the influence of ADQ on mammosphere formation in breast CSCs
Summary
Breast cancer remains the most common malignant cancer among women, and is the second most common cause of death in women, with 8.6 million new cases and 4.2 million related deaths in 2018 (Bray et al, 2018; Byrd et al, 2020; Shieh and Tice, 2020). To improve the overall survival and life quality of patients with breast cancer, multiple strategies have arisen, including surgery, radiotherapy, endocrine, targeted therapy, and chemotherapy (Britt et al, 2020). Chemotherapy involves the generating of pro-metastatic signals, eliciting primary breast cancer cells transferring and seeding into distant pulmonary organs (Minami et al, 2016). TAOK3 is a candidate protein target in breast cancer chemoresistance, which possibly acts by interacting with NFκB, as revealed by kinase short hairpin RNA (shRNA) screening (Lai et al, 2020). KCNN4 promoted gemcitabine resistance in breast cancer models by activating RAS-MAPK and PI3K-AKT signaling and subsequently upregulating of BCL2A1 protein levels, and its expression predicted poor disease-free survival (Lin et al, 2020). Taken together, searching for a novel chemosensitizing therapy may have profound implications for the control and prevention of breast cancer recurrence
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