Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.
Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
J Pharm Sci. 2018 Dec;107(12):3163-3170. doi: 10.1016/j.xphs.2018.08.011. Epub 2018 Aug 23.
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.
SLC22A18 基因位于 11p15.5 印迹区域，该区域是一个重要的肿瘤抑制基因区域，编码一个孤儿转运体。然而，SLC22A18 在肿瘤抑制中的作用尚不清楚。在这里，我们研究了 SLC22A18 对 MCF7 人乳腺癌细胞系细胞生长、侵袭和耐药性的影响。Western blot 分析表明，SLC22A18 主要表达在细胞内细胞器膜上。定量蛋白质组学显示，SLC22A18 敲低显著改变了 1867 种鉴定蛋白中的 578 种（31.0%）的表达，其中包括与乳腺癌恶性程度和不良预后相关的蛋白。SLC22A18 敲低（1）同时增加 MCF7 细胞生长，使膜联蛋白 A8（参与细胞生长和迁移；不良预后的预测因子）增加超过 7 倍，（2）诱导 MCF7 细胞呈球形形态，同时使 CD44 增加近 3 倍（参与调节恶性表型），（3）增加对长春花生物碱的化疗敏感性，同时使双皮质素样激酶 1 减少超过 80%（参与调节微管聚合）。我们的结果表明，SLC22A18 可能通过调节细胞生长相关蛋白的表达水平发挥肿瘤抑制作用，长春花生物碱可能对低表达 SLC22A18 的乳腺癌具有治疗效果。
