Abstract
BackgroundThe Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis. However, the mechanism underlying chemotherapeutic resistance in cancer cells has not been completely elucidated. The NHE1 inhibitor cariporide has been demonstrated to inhibit human cancer cell lines. The goal of this study was to provide new sights into improved cancer cell chemosensitivity mediated by cariporide with activation of the apoptosis pathway.MethodsThe NHE1 expression levels were first evaluated using the online database Oncomine and were determined by RT-PCR and western blot in vitro and in vivo. Cell proliferation was assessed In vitro through a CCK-8 assay, and apoptosis was analyzed by flow cytometry. An in vivo analysis was performed in BALB/c nude mice, which were intraperitoneally injected with MCF-7/ADR cells.ResultsNHE1 levels were significantly higher in breast cancer tissue than adjacent tissue, as well as in resistant cancer cells compared to sensitive cells. Cariporide induced the apoptosis of MCF-7/ADR cells and was associated with the intracellular accumulation of doxorubicin and G0/G1 cell cycle arrest. Moreover, cariporide decreased MDR1 expression and activated cleaved caspase-3 and caspase-9, promoting caspase-independent apoptosis in vitro. In vivo, cariporide significantly improved doxorubicin sensitivity in a xenograft model, enhancing tumor growth attenuation and diminishing tumor volume.ConclusionsOur results demonstrate that cariporide significantly facilitates the sensitivity of breast cancer to doxorubicin both in vitro and in vivo. This finding suggests that NHE1 may be a novel adjuvant therapeutic candidate for the treatment of resistant breast cancer.
Highlights
The Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis
Na+/H+ Exchanger 1 (NHE1) expression varies in breast cancer tissue and cell lines To verify the crucial role of NHE1 in breast cancer, we examined publicly available gene expression datasets, and observed that NHE1 is up-regulated in the majority of breast tumors in three independent datasets, and was associated with poor prognosis (Fig. S1B, S1C)
Strong positive staining gradually increased from ductal carcinoma in situ to invasive ductal carcinoma, which is in accordance with previous findings showing that NHE1 mRNA expression is elevated in invasive breast cancer [22]
Summary
The Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis. The mechanism underlying chemotherapeutic resistance in cancer cells has not been completely elucidated. The NHE1 inhibitor cariporide has been demonstrated to inhibit human cancer cell lines. The goal of this study was to provide new sights into improved cancer cell chemosensitivity mediated by cariporide with activation of the apoptosis pathway. Breast cancer (BC) is one of the most common female malignant neoplasms [1, 2]. Standard first-line adjuvant chemotherapy of breast cancer contains doxorubicin or paclitaxel, leading to remission of patients in the early stages of BC [3]. Increasing evidence had shown that NHE1 plays a crucial role in carcinogenesis, migration, invasion and drug resistance [9]. Previous investigations identified tumor-suppressive effects caused by NHE1 down-regulation in many cancers, such as gastric cancer [10], leukemia [11] and glioma [12], suggesting that it could serve as a therapeutic target for human cancers [13].
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