Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1869, Issue 6, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2023.166727
Keywords
Breast cancer; Chemoresistance; CAFs; TCF12; Autophagy; Exosome
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Cancer-associated fibroblasts (CAFs) are important in tumor progression and chemoresistance. Epirubicin treatment induces ROS and autophagy in CAFs, and TCF12 inhibits autophagy and promotes exosome secretion. Inhibition of ROS production or autophagic initiation reduces exosome release. Exosomes from EPI-treated CAFs not only prevent ROS accumulation but also enhance EPI resistance in breast cancer cells through upregulating CXCR4 and c-Myc protein levels.
Cancer-associated fibroblasts (CAFs) are the predominant stromal cells in the microenvironment and play important roles in tumor progression, including chemoresistance. However, the response of CAFs to chemo-therapeutics and their effects on chemotherapeutic outcomes are largely unknown. In this study, we showed that epirubicin (EPI) treatment triggered ROS which initiated autophagy in CAFs, TCF12 inhibited autophagy flux and further promoted exosome secretion. Inhibition of EPI-induced reactive oxygen species (ROS) production with N-acetyl-L-cysteine (NAC) or suppression of autophagic initiation with short interfering RNA (siRNA) against ATG5 blunted exosome release from CAFs. Furthermore, exosome secreted from EPI-treated CAFs not only prevented ROS accumulation in CAFs but also upregulated the CXCR4 and c-Myc protein levels in recipient ER+ breast cancer cells, thus promoting EPI resistance of tumor cells. Together, the current study provides novel insights into the role of stressed CAFs in promoting tumor chemoresistance and reveal a new function of TCF12 in regulating autophagy impairment and exosome release.
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