AI Article Synopsis

  • - The study investigates how tumor-associated macrophages (TAMs) and their secretion of CXCL1 contribute to autophagy-mediated chemoresistance in breast cancer, which leads to poor treatment outcomes.
  • - It was discovered that blocking CXCL1 increases the sensitivity of breast cancer cells to chemotherapy by inhibiting autophagy, primarily through a mechanism involving IGF1R and its signaling pathways.
  • - The findings link CXCL1 with enhanced autophagy and identify a novel signaling pathway (IGF1R/STAT3/HMGB1) that plays a significant role in cancer progression and patient prognosis, emphasizing the importance of targeting CXCL1 for better treatment strategies.

Article Abstract

Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470078PMC
http://dx.doi.org/10.1038/s41419-024-07123-5DOI Listing

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