Involvement of an Orphan Transporter, SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells

The SLC22A18 gene, which encodes an orphan transporter, is located at the 11p15.5 imprinted region, an important tumor suppressor gene region. However, the role of SLC22A18 in tumor suppression remains unclear. Here, we investigated the involvement of SLC22A18 in cell growth, invasion, and drug resi...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2018-12, Vol.107 (12), p.3163-3170
Main Authors: Ito, Shingo, Fujino, Yu, Ogata, Seiryo, Hirayama-Kurogi, Mio, Ohtsuki, Sumio
Format: Article
Language:English
Subjects:
annexin A8
Antineoplastic Agents - pharmacology
breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
CD44
Cell Proliferation - drug effects
DCLK1
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
MCF-7 Cells
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
Neoplasm Invasiveness - prevention & control
Organic Cation Transport Proteins - genetics
orphan transporter
quantitative proteomics
SLC22A18
vinca alkaloid
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Summary:The SLC22A18 gene, which encodes an orphan transporter, is located at the 11p15.5 imprinted region, an important tumor suppressor gene region. However, the role of SLC22A18 in tumor suppression remains unclear. Here, we investigated the involvement of SLC22A18 in cell growth, invasion, and drug resistance of MCF7 human breast cancer cell line. Western blot analysis indicated that SLC22A18 is predominantly expressed at intracellular organelle membranes. Quantitative proteomics showed that knockdown of SLC22A18 significantly altered the expression of 578 (31.0%) of 1867 proteins identified, including proteins related to malignancy and poor prognosis of breast cancer. SLC22A18 knockdown (1) increased MCF7 cell growth concomitantly with a >7-fold increase of annexin A8 (involved in cell growth and migration; a predictor of poor prognosis), (2) induced spherical morphology of MCF7 cells concomitantly with a nearly 3-fold increase of CD44 (involved in regulation of malignant phenotypes), and (3) increased chemosensitivity to vinca alkaloids concomitantly with a >80% reduction of doublecortin-like kinase 1 (involved in regulation of microtubule polymerization). Our results suggest that SLC22A18 may act as a tumor suppressor by regulating the expression levels of cell growth–related proteins, and vinca alkaloids might show therapeutic efficacy against low-SLC22A18–expressing breast cancer.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2018.08.011