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

Abstract

AbstractL‐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.