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Published on: January 7, 2019
Increased expression of sorcin is associated with multidrug resistance in leukemia cells via up-regulation of MDR1
Nobuyuki Yamagishi1, Ryota Nakao2, Rumi Kondo2
1Department of Biochemistry & Molecular Biology, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan; Radioisotope Center, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Abstract:
Sorcin, a 22 kDa Ca(2+) binding protein, was first identified in a vincristine-resistant Chinese hamster lung cell line, and was later demonstrated to be involved in the development of multidrug-resistance (MDR) phenotypes in a variety of human cancer cell lines. However, the exact role of sorcin in MDR cells is yet to be fully elucidated. Here we explored the role of sorcin in the development of MDR in leukemia cells, and revealed that the expression level of sorcin was directly correlated to the expression of MDR1/P-glycoprotein (P-gp). In addition, it was shown that sorcin induced the expression of MDR1/P-gp through a cAMP response element (CRE) between -716 and -709 bp of the mdr1/p-gp gene. Furthermore, overexpression of sorcin increased the phosphorylation of CREB1 and the binding of CREB1 to the CRE sequence of mdr1/p-gp promoter, and induced the expression of MDR1/P-gp. These findings suggested that sorcin induces MDR1/P-gp expression markedly through activation of the CREB pathway and is associated with the MDR phenotype. The new findings may be helpful for understanding the mechanisms of MDR in human cancer cells, prompting its further investigation as a molecular target to overcome MDR.
Insights
Sorcin protein directly increases multidrug resistance (MDR) in leukemia cells by activating the CREB pathway, which upregulates MDR1/P-glycoprotein (P-gp) expression. This discovery offers new insights into overcoming cancer drug resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Sorcin, a calcium-binding protein, is implicated in multidrug resistance (MDR) phenotypes in various cancer cells.
- The precise role of sorcin in MDR development requires further elucidation, particularly in leukemia.
Purpose of the Study:
- To investigate the role of sorcin in the development of MDR in leukemia cells.
- To identify the molecular mechanisms by which sorcin contributes to MDR.
Main Methods:
- Correlation analysis between sorcin expression and MDR1/P-glycoprotein (P-gp) expression in leukemia cells.
- Investigation of sorcin's effect on the mdr1/p-gp gene promoter activity.
- Assessment of CREB1 phosphorylation and its binding to the mdr1/p-gp promoter.
Main Results:
- Sorcin expression levels directly correlated with MDR1/P-gp expression.
- Sorcin induced MDR1/P-gp expression via a cAMP response element (CRE) in the mdr1/p-gp gene promoter.
- Sorcin overexpression enhanced CREB1 phosphorylation and its binding to the CRE sequence, leading to increased MDR1/P-gp expression.
Conclusions:
- Sorcin significantly induces MDR1/P-gp expression through the activation of the CREB pathway, contributing to the MDR phenotype in leukemia.
- Understanding this sorcin-mediated pathway provides potential molecular targets for overcoming MDR in human cancers.
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