Abstract 7055: Elucidation of the interplay between phospholipid byosynthesis and oxidative stress in the pathogenesis of renal cell carcinoma
Authors: Renpei Kato, Daiki Ikarashi, Shigekatsu Maekawa, Mitsugu Kanehira, Ryo Takata, Yosuke Matsushita, Tetsuro Yoshimaru, Tomoya Fukawa, Toyomasa Katagiri, Wataru Obrara
Journal: Cancer Research (2024)

Abstract Introduction: Renal cell carcinoma (RCC) is a primary malignant kidney tumor. We reported on the critical role of Protein of Relevant Evolutionary and Lymphoid Interest Domain 2 (PRELID2) in cell proliferation, emphasizing its regulatory function on mitochondrial ROS and maintenance of mitochondrial spare respiratory capacity. Recent studies have begun to clarify the molecular mechanism of phospholipid biosynthesis by PRELID1 and PRELID3 under oxidative stress conditions. Inspired by this evidence, we analyzed the relationship between PRELID2 and phospholipid biosynthesis, aiming to elucidate the molecular mechanism of PRELID2 related to the control of mitochondrial ROS. Methods: To analyze the dynamics of phospholipids and related mitochondrial molecules induced by oxidative stress, we examined the expression of YME1L and its substrates (OPA1, PRELID1) using Western blotting, which has been shown to be related to the turnover of other PRELI family proteins. Lipidomic analysis was performed using LC-MS on samples from HEK293 cells with stable expression of PRELID2 and control cells, as well as renal carcinoma cell lines with suppressed PRELID2 expression using siRNA and control cells. Additionally, we analyzed the expression of mitochondrial respiratory chain complexes Cytochrome C and COX4 and their relationship with PRELID2 expression via Western blotting. Results: Oxidative stress led to a noticeable decline in YME1L expression, which was correlated with decreased OPA1 and PRELID1 levels in control cells. Conversely, PRELID2-overexpressing cells retained stable expression of OPA1 and PRELID1. Furthermore, these cells exhibited a significant reduction in phosphatidyl glycerol (PG) levels. Suppressing PRELID2 expression in 786-O cells using siRNA resulted in significantly higher PG levels. When analyzing the molecules of the mitochondrial respiratory chain during oxidative stress induction, we observed that although oxidative stress induced a decline in cytochrome C expression in control cells, it remained consistent in PRELID2-expressing cells. However, PRELID2 expression did not affect COX4 levels. Conclusions: Our findings underscore the pivotal role of PRELIDs in maintaining mitochondrial homeostasis, proving instrumental in the oxidative stress-driven progression of renal cancer. Citation Format: Renpei Kato, Daiki Ikarashi, Shigekatsu Maekawa, Mitsugu Kanehira, Ryo Takata, Yosuke Matsushita, Tetsuro Yoshimaru, Tomoya Fukawa, Toyomasa Katagiri, Wataru Obrara. Elucidation of the interplay between phospholipid byosynthesis and oxidative stress in the pathogenesis of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7055.