TY - JOUR
T1 - Involvement of an Orphan Transporter, SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells
AU - Ito, Shingo
AU - Fujino, Yu
AU - Ogata, Seiryo
AU - Hirayama-Kurogi, Mio
AU - Ohtsuki, Sumio
N1 - Funding Information:
This study was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science (JSPS) for Research Activity Start-up (No. 24890170), Young Scientific Research(B) (No. 26860109) and Scientific Research (C) (No. 16K08373), and the Takeda Science Foundation.
Publisher Copyright:
© 2018 American Pharmacists Association®
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - annexin A8
KW - breast cancer
KW - CD44
KW - DCLK1
KW - orphan transporter
KW - quantitative proteomics
KW - SLC22A18
KW - vinca alkaloid
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U2 - 10.1016/j.xphs.2018.08.011
DO - 10.1016/j.xphs.2018.08.011
M3 - Article
C2 - 30145211
AN - SCOPUS:85054153001
SN - 0022-3549
VL - 107
SP - 3163
EP - 3170
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 12
ER -
