The chemosensitizing activity of betulinic acid in suppressing macrophage polarization through GSK-3β/β-catenin/CXCL1 signaling in breast cancer.

Background: Autophagy-induced chemoresistance constitutes a principal mechanism underlying therapeutic inefficacy and adverse prognoses in breast cancer. It has been demonstrated that the resistance to chemotherapy in breast cancer is modulated by tumor-associated macrophages (TAMs), with the C-X-C motif chemokine ligand 1 (CXCL1) being identified as the predominant cytokine secreted by these cells. Betulinic acid (BA), a pentacyclic triterpenoid naturally present in plant resources such as birch bark and jujube seeds, and also derived from the Traditional Chinese Medicinal herb Scleromitrion diffusum (Willd.) R.J. Wang has proven notable efficacy in combating breast cancer. However, the effect and mechanism of BA on the chemosensitization of breast cancer are yet to be determined.

Purpose: This study aimed to provide evidence indicating that BA could reduce the expression of TAMs/CXCL1 through the GSK-3β/β-catenin signaling pathway, consequently augmenting the chemosensitivity of breast cancer cells.

Methods: This study investigated the role of BA in enhancing the chemosensitivity of breast cancer by modulating TAM-induced autophagy, employing both in vitro and in vivo models. The underlying mechanisms were explored through the application of gene recombination technology, antibody microarray analysis and detection of the proteasome degradation pathway.

Results: BA was found to markedly impede the polarization of M2-TAMs and the secretion of CXCL1, resulting in diminished chemoresistance in breast cancer cells. Further mechanistic studies revealed that BA targeted the GSK-3β/β-catenin signaling to downregulate CXCL1 expression, thereby suppressing the AMPK/mTOR/Beclin 1 autophagy pathway. Through the ex vivo zebrafish and in vivo murine models, we demonstrated the chemosensitizing properties of BA and its ability to counteract TAM-induced chemoresistance.

Conclusion: This study identifies BA as a novel chemosensitizer that targets TAM-mediated autophagy through the GSK-3β/β-catenin/CXCL1 axis, offering a new therapeutic strategy to overcome chemoresistance in breast cancer.