scholarly journals Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769222 ◽  
Author(s):  
Ji Yang ◽  
Yue Wu ◽  
Xiao Wang ◽  
Liqian Xu ◽  
Xiaohong Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Breast Cancer Cells ◽  
Acquired Resistance ◽  
Specific Protein ◽  
Drug Resistant ◽  
Standard Chemotherapy ◽  
Protein X ◽  
The Common

Acquired resistance to standard chemotherapy is the common and critical limitation for cancer therapy. Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) has been reported to be upregulated in numerous cancers. However, the role of HAX-1 in oncotherapy remains unclear. In this study, we established MDA-MB-231 cell lines which were resistant to cisplatin (MDA-MB-231/CR) or doxorubicin (MDA-MB-231/DR) to study the chemoresistance in breast cancer. As a result, the HAX-1 which is an apoptosis-associated protein was observed to be overexpressed in both MDA-MB-231/CR and MDA-MB-231/DR compared with the routine MDA-MB-231 cells. Moreover, knockdown of HAX-1 via RNA interference decreased IC50 level of cisplatin by 70.91% in MDA-MB-231/CR cells, and the IC50 level of doxorubicin was decreased by 76.46% in MDA-MB-231/DR cells when the HAX-1 was downregulated. Additionally, we found that the knockdown of HAX-1 induced the release of cytochrome C from mitochondria, resulting in the activation of caspases. Taken together, our study indicates that the overexpression of HAX-1 is essential in the development of chemoresistance in breast cancer. Furthermore, we identify that HAX-1 may become the target for cancer therapy.

scholarly journals Effect of the exosome-mediated suppression of the estrogen signaling: the role in the progression of the hormonal resistance of breast cancer cells

2020 ◽  
Vol 7 (3) ◽  
pp. 58-62
Author(s):  
D. V. Sorokin ◽  
O. E. Andreeva ◽  
E. I. Mikhaevich ◽  
Yu. Yu. Shchegolev ◽  
A. M. Scherbakov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Acquired Resistance ◽  
Estrogen Signaling ◽  
Aromatase Inhibitor Treatment ◽  
Hormonal Resistance ◽  
Exosomal Microrna ◽  
Inhibitor Treatment

The most effective treatment of the hormone-dependent breast cancer is based on the antiestrogens SERM and aromatase inhibitor treatment, however its efficiency is limited by the acquired resistance to the drugs.Previously we have revealed the effect of the transferring of the hormonal resistance from the resistant to the sensitive cells under in vitro cell co-cultivation, and demonstrated exosomes involvement in this process. Here we have shown that the exosomes of the resistant cells caused the marked inhibition of the estrogen signaling in the recipient cells, and identified microRNAs – ERα suppressors that overexpressed in the resistant exosomes.Taken together, the results obtained demonstrate the important role of the estrogen signaling suppression in the exosome-induced transferring of the hormonal resistance, and revealed the involvement of the exosomal microRNA in the ERα down-regulation.

scholarly journals Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species

2021 ◽  
Vol 9 ◽  
Author(s):  
He Zhang ◽  
Xingxing Han ◽  
Zhaosong Wang ◽  
Zhiyong Wang ◽  
Yanfen Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Intracellular Reactive Oxygen Species ◽  
Drug Resistant ◽  
Oxygen Species ◽  
Drug Pump ◽  
Resistant Cells

ATP-binding cassette (ABC) transporter family are major contributors to the drug resistance establishment of breast cancer cells. Breast cancer resistant protein (BCRP), one of the ABC transporters, has long been recognized as a pump that effluxes the therapeutic drugs against the concentration gradient. However, recent studies suggest that the biological function of BCRP is not limited in its drug pump activity. Herein, the role of BCRP in the proliferation and survival of drug-resistant breast cancer cells was investigated. We found that BCRP is not the major drug pump to efflux epirubicin in the resistant cells that express multiple ABC transporters. Silencing of BCRP significantly impairs cell proliferation and induces apoptosis of the resistant cells in vitro and in vivo. RNA-sequencing and high-throughput proteomics suggest that BCRP is an inhibitory factor of oxidative phosphorylation (OXPHOS). Further research suggests that BCRP is localized in the mitochondria of the resistant cells. Knockdown of BCRP elevated the intracellular reactive oxygen species level and eventually promotes the cell to undergo apoptosis. This study demonstrated that BCRP exerts important onco-promoting functions in the drug-resistant breast cancer cells independent of its well-recognized drug efflux activity, which shed new light on understanding the complex functional role of ABC transporters in drug-resistant cells.

scholarly journals Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

2020 ◽  
Author(s):  
Zicong Gao ◽  
Xingxing Han ◽  
Yuying Zhu ◽  
He Zhang ◽  
Ran Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Resistant Cell ◽  
Migration And Invasion ◽  
Drug Resistant ◽  
Resistant Cells

Abstract Background: The failure of chemotherapy is accompanied by the emergence of drug resistance and tumor relapse. Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. In this study, we aimed to investigate the mechanisms of exosomes derived from drug-resistant cells in regulating the invasion and metastasis of sensitive breast cancer cells.Methods: Exosomes isolated from drug-resistant breast cancer cells and their parental cells were used to treat breast cancer cells, and then the migration and invasion abilities were examined. The tandem mass tag (TMT)-based quantitative proteomic method was carried out to identify key molecules that regulate cancer aggressiveness. Lentivirus-mediated shRNAs, overexpression, point mutation, truncation mutation, Western blotting, tumor xenograft mice models, and in vivo breast cancer metastatic models were used to investigate the functional role of EphA2 on the invasion and metastatic potential of breast cancer cells.Results: We demonstrated that drug-resistant cell-derived exosomes promoted the migration and invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. In addition, we provided considerable evidence that exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Conclusions: Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

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