Changes in subcellular localization of Lysyl-tRNA synthetase and the 67-kDa laminin receptor in epithelial ovarian cancer metastases

Article type: Research Article

Authors: Lee, Dae Hoon^{a; b; 1} | Paik, E. Sun^{c; 1} | Cho, Young-Jae^{d; 1} | Lee, Yoo-Young^d | Lee, Bada^{a; b} | Lee, Eui Jin^{a; b} | Choi, Jung-Joo^d | Choi, Chel-Hun^d | Lee, Sangmin^a | Choi, Jin Woo^{a; b; e; *} | Lee, Jeong-Won^{d; *}

Affiliations: [a] Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, Korea | [b] Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Korea | [c] Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea | [d] Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea | [e] Department of Regulatory Science, College of Pharmacy, Kyung Hee University, Seoul, Korea

Correspondence: [*] Corresponding authors: Jin Woo Choi, Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, Korea. E-mail: jinwoo.ch@khu.ac.kr. Jeong-Won Lee, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. E-mail: garden.lee@samsung.com.

Note: [1] Dae Hoon Lee, E. Sun Paik and Young-Jae Cho contributed equally to this work as co-first authors.

Abstract: BACKGROUND: Although lysyl-tRNA synthetase (KARS1) is predominantly located in the cytosol, it is also present in the plasma membrane where it stabilizes the 67-kDa laminin receptor (67LR). This physical interaction is strongly increased under metastatic conditions. However, the dynamic interaction of these two proteins and the turnover of KARS1 in the plasma membrane has not previously been investigated. OBJECTIVE: Our objective in this study was to identify the membranous location of KARS1 and 67LR and investigate if this changes with the developmental stage of epithelial ovarian cancer (EOC) and treatment with the inhibitor BC-K01. In addition, we evaluated the therapeutic efficacy of BC-K01 in combination with paclitaxel, as the latter is frequently used to treat patients with EOC. METHODS: Overall survival and prognostic significance were determined in EOC patients according to KARS1 and 67LR expression levels as determined by immunohistochemistry. Changes in the location and expression of KARS1 and 67LR were investigated in vitro after BC-K01 treatment. The effects of this compound on tumor growth and apoptosis were evaluated both in vitro and in vivo. RESULTS: EOC patients with high KARS1 and high 67LR expression had lower progression-free survival rates than those with low expression levels of these two markers. BC-K01 reduced cell viability and increased apoptosis in combination with paclitaxel in EOC cell xenograft mouse models. BC-K01 decreased membranous KARS1 expression, causing a reduction in 67LR membrane expression in EOC cell lines. BC-K01 significantly decreased in vivo tumor weight and number of nodules, especially when used in combination with paclitaxel. CONCLUSIONS: Co-localization of KARS1 and 67LR in the plasma membrane contributes to EOC progression. Inhibition of the KARS1-67LR interaction by BC-K01 suppresses metastasis in EOC.

Keywords: Laminin receptor, lysyl-tRNA synthetase, cancer metastasis, anticancer agent, protein-protein interaction

DOI: 10.3233/CBM-210077

Journal: Cancer Biomarkers, vol. 35, no. 1, pp. 99-109, 2022