Characterization of the Cancer Stem Cell Phenotype in Bone Metastatic Breast Cancer and Its Treatment with Gli2 Inhibitor
Castillo, Kristopher
0009-0002-8427-5302
:
2023-07-21
Abstract
Tumor-induced bone disease (TIBD) is associated with severe morbidities and reduced survival rates in metastatic cancer patients. Gli2 transcription factor plays a critical role in bone metastasis and TIBD by promoting parathyroid hormone (PTH) release, enhancing osteoclast activity and bone resorption. Moreover, Gli2 is implicated in chemoresistance, although the mechanistic role of Gli2 in CSCs remains unclear. In this study, we investigated the link between Gli2, bone metastasis, CSC enrichment, and chemoresistance. Using CD44high/CD24low and ALDH1+ cancer cells as breast CSC markers, we examined their expressions in primary tumor cells and bone metastatic cells. Flow cytometry and western blot analysis revealed an enrichment of ALDH1+ CSC populations in bone metastatic cells with an upregulation of Gli2 activity. To investigate the impacts of Gli2 on bone metastasis, CSCs, and chemoresistance, we employed GANT58, a Gli2 inhibitor, in combination with paclitaxel (PTX), a front-line anti-cancer drug used to treat bone metastasis. We found that a 10:1 combination of GANT58 to PTX exhibits synergy in vitro. Breast cancer cells treated with PTX, GANT58, or synergistic combination were allowed to incubate for 72 hours, followed by analysis of Gli2 and ALDH1+ expressions. We found significantly reduced enrichment of ALDH1+ CSC populations and reduced Gli2 activity. Taken together, these results support the notion that chemoresistance of breast CSCs may be driven by Gli2 activity, and that PTX/GANT58 combination may be a useful CSC-targeting strategy for metastatic breast cancer.
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