Abstract
Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44(+)/CD24(-) and ALDH1(high) cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / secondary*
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Adenocarcinoma of Lung
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Aldehyde Dehydrogenase 1 Family
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Animals
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Antibiotics, Antineoplastic / therapeutic use
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Antineoplastic Agents, Phytogenic / therapeutic use
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Breast Neoplasms / genetics*
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CD24 Antigen / biosynthesis
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Calcium-Binding Proteins / genetics*
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Cell Movement / genetics
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Cell Proliferation
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm / genetics
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Epithelial-Mesenchymal Transition / genetics*
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Etoposide / therapeutic use
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Female
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Fibrosarcoma / genetics
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Fibrosarcoma / secondary*
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Gene Expression Regulation, Neoplastic
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Humans
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Hyaluronan Receptors / biosynthesis
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Isoenzymes / biosynthesis
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Lung Neoplasms / genetics
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Lung Neoplasms / secondary*
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MCF-7 Cells
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Mice
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Mice, Nude
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Neoplasm Invasiveness / genetics
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Neovascularization, Pathologic / genetics
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RNA Interference
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RNA, Small Interfering
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Retinal Dehydrogenase / biosynthesis
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Spheroids, Cellular / cytology
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents, Phytogenic
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CD24 Antigen
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CD24 protein, human
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CD44 protein, human
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Calcium-Binding Proteins
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Hyaluronan Receptors
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Isoenzymes
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RNA, Small Interfering
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SRI protein, human
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Etoposide
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Doxorubicin
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Aldehyde Dehydrogenase 1 Family
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ALDH1A1 protein, human
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ALDH1A1 protein, mouse
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Retinal Dehydrogenase