Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma

In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various canc...

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Published in:Biochemical and biophysical research communications 2022-06, Vol.611, p.99-106
Main Authors: Kawakami, Issei, Yoshino, Hirofumi, Fukumoto, Wataru, Tamai, Motoki, Okamura, Shunsuke, Osako, Yoichi, Sakaguchi, Takashi, Inoguchi, Satoru, Matsushita, Ryosuke, Yamada, Yasutoshi, Tatarano, Shuichi, Nakagawa, Masayuki, Enokida, Hideki
Format: Article
Language:English
Subjects:
Amino Acid Transport System ASC - genetics
Amino Acid Transport System ASC - metabolism
Carcinoma, Renal Cell - genetics
Cell Line, Tumor
Cell Proliferation
Cellular Senescence
Gene Expression Regulation, Neoplastic
Glutamine - metabolism
Glutamine transporter
Humans
Kidney Neoplasms - genetics
Minor Histocompatibility Antigens - genetics
Renal cell carcinoma
RNA, Small Interfering - genetics
Solute carrier family 1 member 5
V9302
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Summary:In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC. •Solute carrier family 1 member 5 (SLC1A5) is a prognostic factor for poor survival in ccRCC.•SLC1A5 -KO suppressed ccRCC cell proliferation, migration, and invasion in vitro•Inhibition of SLC1A5 had antitumor effects in vitro and in vivo.•SLC1A5 inhibition increased ROS levels and induced cellular senescence.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2022.04.068