Inhibition of Bone Marrow-Mesenchymal Stem Cell-Induced Carbonic Anhydrase IX Potentiates Chemotherapy Efficacy in Triple-Negative Breast Cancer Cells

Abstract

Conventional chemotherapy represents the main systemic treatment used for triple-negative breast cancer (TNBC) patients, although many of them develop drug resistance. The hypoxic TME is the crucial driver in the onset of insensitivity to chemotherapy. In this research, we elucidated the role played by bone marrow-derived mesenchymal stem cells (BM-MSCs) in reducing cisplatin effects in TNBC. BT-549 and MDA-MB-231 cells, grown under hypoxic conditions in the presence of conditioned medium obtained from BM-MSCs (CM-MSCs), showed a strong cisplatin insensitivity and increased expression levels of carbonic anhydrase IX (CA IX). Therefore, we inhibited CM-MSC-induced CA IX by SLC-0111 to potentiate chemotherapy efficacy in TNBC cells. Our results showed that CM-MSCs under hypoxic conditions caused an increase in the ability of TNBC cells to form vascular structures, migrate and invade Matrigel. Cell treatment with cisplatin plus SLC-0111 was able to block these mechanisms, as well as the signaling pathways underlying them, such as p-AKT, p-ERK, CD44, MMP-2, vimentin, β-catenin, and N-cadherin, more effectively than treatment with single agents. In addition, a significant enhancement of apoptosis assessed by annexin V, caspase-3 expression and activity was also shown. Taken together, our results demonstrated the possibility, through CA IX inhibition, of returning TNBC cells to a more chemosensitive state.

Metadherin inhibits chemosensitivity of triple‐negative breast cancer to paclitaxel via activation of AKT/GSK‐3β signaling pathway

“…Similarly, it was demonstrated that MTDH overexpression reduced sensitivity to gemcitabine, while MTDH knockdown significantly promoted the chemosensitivity effect (Li et al., 2021). Moreover, in our previous studies, we found that MTDH overexpression enhanced the resistance of TNBC cells to doxorubicin (Sarnella et al., 2023) and was related to PTX chemotherapeutic drug resistance (Nguyen et al., 2020). Our study also showed that MTDH knockdown increased chemosensitivity to PTX in TNBC.…”

“…Assays were performed in strict accordance with the manufacturer's instructions. Briefly, cells were fixed with 75% ethanol at 4°C overnight (Sarnella et al., 2023). The fixed cells were washed with PBS (phosphate‐buffered saline) and suspended in 200 μL RNase A at 37°C for 10 min, and 250 μL PI (propidium iodide 100 μg/mL) was added to stain the DNA of the cells in the dark for 15 min.…”

Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells

“…Next, we analyzed TIMP-1 expression levels in two MDA-MB-231 derivative cell lines, indicated as Dox-R and Cis-Pt-R, that we generated by chronic treatment of parental cells with Dox and Cis-Pt, respectively [ 38 , 39 ]. Both Dox-R and Cis-Pt-R cell lines, compared with the parental cells, show an increased chemoresistance ( Figure 1 B) and express higher levels of mesenchymal/stem cell markers as integrin αv [ 38 , 47 , 48 , 49 ], PDGFRβ [ 46 , 50 ], vimentin [ 51 ], CD99 [ 52 , 53 ] and CD44 [ 54 ], and lower levels of ZO-1 epithelial cell marker [ 55 ], reflecting their mesenchymal/stem-like phenotype ( Figure 1 C). Interestingly, TIMP-1 expression in both highly chemoresistant cell lines was significantly higher than in parental MDA-MB-231 cells ( Figure 1 C).…”

Carbonic Anhydrase IX Enzyme in Triple Negative Breast Carcinoma: Relationship with prognostic factors and response to neoadjuvant chemotherapy

“…Resistance to treatment leads to recurrence and distant metastasis in 40-80% of cases, resulting in death. The tumor microenvironment has been identi ed as one of the parameters in uencing treatment response, emphasizing its importance in tumor development, growth, metastasis, recurrence, and treatment response (20,21). Recent studies have demonstrated that the hypoxic tumor microenvironment, in uenced by CA IX, affects tumor growth, invasion, and treatment resistance [13,[21][22][23].…”