연구성과 홍보

Chem Biol Interact. 2024 Aug 1:398:111089.

Title : Integrative multi-omics analysis reveals ortho-topolin riboside exhibits anticancer activity by regulating metabolic pathways in radio-resistant triple negative breast cancer cells

Authors : Junyoung Ahn1, Ji Won Lee1, Seung Min Nam1, Dae Kyeong Kim2, Somi Kim Cho3*, Hyung-Kyoon Choi4*

Affiliations :

1College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.

2Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, 63243, Republic of Korea.

3Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, 63243, Republic of Korea; Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju, 63243, Republic of Korea.

4College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.

DOI: 10.1016/j.cbi.2024.111089.

Abstract :

Radio-resistant triple negative breast cancer (TNBC) is resistant to conventional drugs and radiation therapy. ortho-topolin riboside (oTR) has been evaluated for its anticancer activity in several types of cancer cells. However, its anti-proliferative activity in radio-resistant TNBC cells has not yet been reported. Therefore, we investigated the anti-proliferative activity of oTR in radio-resistant TNBC cells, and performed metabolome, lipidome, transcriptome, and proteome profiling to reveal the mechanisms of the anticancer activity of oTR. oTR showed cytotoxicity against radio-resistant TNBC cells with an inhibitory concentration (IC50) value of 7.78 μM. Significantly decreased (p value < 0.05) basal and compensatory glycolysis were observed in the oTR-treated group than untreated group. Mitochondrial spare respiratory capacity, which is relevant to cell fitness and flexibility, was significantly decreased (p value < 0.05) in the oTR-treated group. The major metabolic pathways significantly altered by oTR according to metabolome, transcriptome, and proteome profiles were the glycerolipid/glycerophospholipid pathway (log2(FC) of MGLL = -0.13, log2(FC) of acylglycerol lipase = -1.35, log2(FC) of glycerol = -0.81), glycolysis (log2(FC) of EGLN1 = 0.16, log2(FC) of EGLN1 = 0.62, log2(FC) of glucose = -0.76, log2(FC) of lactate = -0.81), and kynurenine pathway (log2(FC) of KYNU = 0.29, log2(FC) of kynureninase = 0.55, log2(FC) of alanine = 0.72). Additionally, proline metabolism (log2(FC) of PYCR1 = -0.17, log2(FC) of proline = -0.73) was significantly altered in the metabolomic and transcriptomic profiles. The MAPK signaling pathway (log2(FC) of CCN1 = -0.15, log2(FC) of CCN family member 1 = -1.02) and Rap 1 signaling pathway (log2(FC) of PARD6B = -0.28, log2(FC) of PAR6B = -3.13) were also significantly altered in transcriptomic and proteomic profiles. The findings of this study revealed that oTR has anticancer activity in radio-resistant TNBC cells by affecting various metabolic pathways, suggesting the potential of oTR as a novel anticancer agent for radio-resistant TNBC patients.