Inhibition of sorcin reverses multidrug resistance of K562/A02 cells and MCF-7/A02 cells via regulating apoptosis-related proteins

Hu, Yunhui; Cheng, Xin; Li, Shuangjing; Zhou, Yuan; Wang, Jianxiang; Cheng, Tao; Yang, Moon-Sik; Xiong, Dongsheng

doi:10.1007/s00280-013-2254-2

Cited by 35 publications

(33 citation statements)

References 29 publications

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“…Previous studies indicated that overexpression of Sorcin is associated with resistance in human ovarian, breast cancer, lung cancer, leukemia and gastric carcinoma (6). Downregulation of Sorcin expression in K562/A02 cells, which are resistant to doxorubicin, restored drug sensitivity (7)(8)(9). These findings suggest that Sorcin may be a potential therapeutic target for reversing MDR in cancer.…”

Section: Introductionmentioning

confidence: 74%

Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

Gao

Liu

et al. 2014

Molecular Medicine Reports

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Abstract. Lung cancer is the primary malignancy of the lung and is the leading cause of cancer-associated mortality in China. Multidrug resistance (MDR) is an essential aspect of lung cancer treatment failure and a popular topic of investigation in tumor studies. Previous studies have demonstrated that soluble resistance-related calcium-binding protein (Sorcin) is involved in the MDR of various types of human tumor, and that silencing Sorcin was able to reverse the MDR of several types of cultured human cancer cells. However, the effect and potential mechanism underlying the ability of Sorcin to reverse MDR in human lung cancer remains to be fully elucidated. The present study examined the role of Sorcin in the reversal of MDR in human lung cancer A549/DDP cells. The effects included increased drug sensitivity to cisplatin, apoptotic rate, cell cycle arrest in the G2/M phase and intracellular accumulation of rhodamine-123, and decreased expression of multidrug resistance gene 1, lung resistance protein, multidrug resistance-associated protein, glutathione S-transferase π, ATP-binding cassette transporter A2 (ABCA2), ABCA5, B-cell lymphoma 2 and P-glycoprotein, and the depletion of glutathione in Sorcin-silenced A549/DDP cells. The present study also revealed that there was a downregulation of p-Akt and phosphorylated extracellular signal-regulated kinase (p-ERK), and a decreased transcriptional activation of nuclear factor κB, signal transducer and activator of transcription (STAT)3, STAT5 and nuclear factor of activated T-cells following silencing of Sorcin. The results indicated that Sorcin may be used as a potential therapeutic target for MDR through inhibiting the Akt and ERK pathways in human lung cancer.

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Section: Introductionmentioning

confidence: 74%

Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

Gao

Liu

et al. 2014

Molecular Medicine Reports

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“…In order to characterize the role of miRNAs in breast cancer drug resistance, we applied high-throughput miRNA microarray analysis to obtain a miRNA signature of drug resistant MCF-7/A02 breast cancer cells. These cells have been generated from MCF-7 cells, an estrogen receptor-positive line, by exposure to doxorubicin and they are resistant to drugs such as taxol, etoposide, vincristine and mitoxantrone [21]. We identified 16 miRNAs differentially regulated (9 up and 7 down) in MCF-7/A02 cells, including miR-130b, miR-19a, miR-222, miR-218, miR-425 and miR-452.…”

Section: Discussionmentioning

confidence: 99%

“…Two breast cancer cell lines, MCF-7/A02 and CALDOX, were derived from the chemosensitive cell lines MCF-7 and Cal51, respectively, by their resistance to doxorubicin, a common chemotherapeutic used in many cancer treatments [18,21].…”

Section: Microrna Signature Of Drug Resistant Breast Cancer Cellsmentioning

confidence: 99%

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miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

Yagüe

2015

Breast Cancer Res Treat

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Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). Some miRNAs are indicators of drug resistance and confer resistance to chemotherapeutic drugs, although our understanding of this complex process is still incomplete. We have used a combination of miRNA profiling and real-time PCR in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by retroviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related proteins bcl-2 and bax by real-time PCR and Western blot. miR target was studied using transient transfection of luciferase constructs with the 3 untranslated regions (UTR) of target mRNAs. Small interfering RNA-mediated genetic knock-down was performed in MDR cells and its modulatory effect on apoptosis examined. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. miRNA profiling of two drug-resistant breast cancer cell models indicated that miR-218 was down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-218 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-218 binds survivin (BIRC5) mRNA 3-UTR and down-regulated reporter luciferase activity. Experimental down-regulation of survivin by RNA interference in drug-resistant cells did mimic the sensitization observed when miRNA-218 was up-regulated. In addition, resensitization to taxol was also observed in mouse tumor xenografts from cells over-expressing miR-218. miR-218 is involved in the development of MDR in breast cancer cells via targeting survivin and leading to evasion of apoptosis. Targeting miR-218 and survivin may thus provide a potential strategy for reversing drug resistance in breast cancer

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“…For cell cycle analysis cells were stained with propidium iodide after fixation with ice-cold 70% methanol and the DNA content estimated determined by flow cytometry essentially as described (23). Annexin V staining was determined by flow cytometry using an Annexin V-FITC apoptosis detection kit (BioVision) as described (25).…”

Section: Cellsmentioning

confidence: 99%

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

Asaduzzaman

et al. 2015

Oncology Reports

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Abstract. MicroRNA (miR)-106b~25 cluster regulates bypass of doxorubicin and γ-radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106~25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b~25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b~25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b~25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b~25 cluster controls transporter-independent MDR by apoptosis evasion via downregulation of EP300.

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Inhibition of sorcin reverses multidrug resistance of K562/A02 cells and MCF-7/A02 cells via regulating apoptosis-related proteins

Abstract: This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer, especially for the reversal of MDR.

Cited by 35 publications

References 29 publications

Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

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