Abstract
Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.
Highlights
Paclitaxel (PTX) is a common chemical drug for breast cancer (BC) treatment (Yu et al, 2020; Schmid et al, 2020a,b); the therapeutic efficiency of this chemical drug is seriously limited as the results of PTX resistance have been a huge health burden for BC patients worldwide (Chi et al, 2019; Gupta et al, 2019)
The PTX-sensitive BC (PS-BC) cells and PTX-resistant BC (PR-BC) cells were initially subjected to high-dose PTX (50 μg/ml) exposure for 24 h, and we surprisingly found that PTX increased the LC3B-II/I ratio and down-regulated p62 in PR-BC cells, instead of the PS-BC cells (Figures 1E–J)
We evidenced that BC stem cells (BCSCs) were significantly enriched in the PR-BC cell population, instead of their corresponding parental PS-BC cells
Summary
Paclitaxel (PTX) is a common chemical drug for breast cancer (BC) treatment (Yu et al, 2020; Schmid et al, 2020a,b); the therapeutic efficiency of this chemical drug is seriously limited as the results of PTX resistance have been a huge health burden for BC patients worldwide (Chi et al, 2019; Gupta et al, 2019). ANXA6-Exosomes Promote PTX-Resistance properties to PTX treatment are complicated, and researchers agree that cell stemness (Yan et al, 2018; Mori et al, 2019) and autophagy (Zhang et al, 2015; Datta et al, 2019) are two major factors that contribute to this process. PTX treatment initially kills almost all the PTX-sensitive BC (PS-BC) cells, while a subgroup of BC cells with CSC properties survive, which further differentiate into cancer cells with PTX resistance (Yan et al, 2018; Mori et al, 2019). Data from Xu et al (2019), Liu et al (2020) and Yang et al (2020) evidence that blockage of autophagy efficiently promotes PTX sensitivity in BC
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