L‐type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel‐resistant prostate cancer by inhibiting cyclin‐dependent kinase activity

L‐type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating cast...

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Bibliographic Details
Published in:Cancer science 2024-03, Vol.115 (3), p.937-953
Main Authors: Rii, Junryo, Sakamoto, Shinichi, Mizokami, Atsushi, Xu, Minhui, Fujimoto, Ayumi, Saito, Shinpei, Koike, Hidekazu, Tamura, Takaaki, Arai, Takayuki, Yamada, Yasutaka, Goto, Yusuke, Sazuka, Tomokazu, Imamura, Yusuke, Suzuki, Kazuhiro, Kanai, Yoshikatsu, Anzai, Naohiko, Ichikawa, Tomohiko
Format: Article
Language:English
Subjects:
amino acid transporter
Amino acids
Antineoplastic drugs
Benzoxazoles
Castration
CDK
Cell cycle
Cell growth
Cell Line, Tumor
Cell proliferation
Chemotherapy
Chromatography
Cyclin-dependent kinase
Cyclin-dependent kinases
Cyclin-Dependent Kinases - metabolism
Drug resistance
Humans
Kinases
Large Neutral Amino Acid-Transporter 1 - metabolism
LAT1
Liquid chromatography
Male
Mass spectrometry
Mass spectroscopy
Medical research
Metastasis
phosphoproteomics
Phosphorylation
Polymerase chain reaction
Prostate cancer
Prostatic Neoplasms - drug therapy
Proteins
Scientific imaging
Taxoids
Therapeutic targets
Tyrosine - analogs & derivatives
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Summary:L‐type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration‐resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1‐specific inhibitor, JPH203, in cabazitaxel‐resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel‐resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel‐resistant strains in vitro. Phosphoproteomics using liquid chromatography‐mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle‐related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin‐dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel‐resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel‐resistant prostate cancer. JPH203, a specific inhibitor of the amino acid transporter LAT1, was administered to cabazitaxel‐resistant prostate cancer cells to confirm its antitumor effect. Furthermore, using phosphoproteomic analysis, we demonstrated that the activity of CDK as a kinase was significantly reduced by JPH203 treatment.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.16062