Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
The Brown Foundation Institute of Molecular Medicine, University of Texas at Houston Health Science Center, Houston, TX 77030, USA.
Front Biosci (Landmark Ed). 2023 Sep 26;28(9):227. doi: 10.31083/j.fbl2809227.
Colorectal cancer (CRC) is one of the major causes of cancer-related mortality worldwide. The tumor microenvironment plays a significant role in CRC development, progression and metastasis. Oxidative stress in the colon is a major etiological factor impacting tumor progression. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial member of the heat shock protein 90 (HSP90) family that is involved in modulating apoptosis in colon cancer cells under oxidative stress. We undertook this study to provide mechanistic insight into the role of TRAP1 under oxidative stress in colon cells.
We first assessed the The Cancer Genome Atlas (TCGA) CRC gene expression dataset to evaluate the expression of TRAP1 and its association with oxidative stress and disease progression. We then treated colon HCT116 cells with hydrogen peroxide to induce oxidative stress and with the TRAP1 inhibitor gamitrinib-triphenylphosphonium (GTPP) to inhibit TRAP1. We examined the cellular proteomic landscape using liquid chromatography tandem mass spectrometry (LC-MS/MS) in this context compared to controls. We further examined the impact of treatment on DNA damage and cell survival.
TRAP1 expression under oxidative stress is associated with the disease outcomes of colorectal cancer. TRAP1 inhibition under oxidative stress induced metabolic reprogramming and heat shock factor 1 (HSF1)-dependent transactivation. In addition, we also observed enhanced induction of DNA damage and cell death in the cells under oxidative stress and TRAP1 inhibition in comparison to single treatments and the nontreatment control.
These findings provide new insights into TRAP1-driven metabolic reprogramming in response to oxidative stress.
结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。肿瘤微环境在 CRC 的发展、进展和转移中起着重要作用。结肠中的氧化应激是影响肿瘤进展的主要病因学因素。肿瘤坏死因子受体相关蛋白 1（TRAP1）是热休克蛋白 90（HSP90）家族的线粒体成员，参与调节结肠癌细胞在氧化应激下的细胞凋亡。我们进行这项研究是为了深入了解 TRAP1 在结肠细胞氧化应激下的作用机制。
我们首先评估了癌症基因组图谱（TCGA）CRC 基因表达数据集，以评估 TRAP1 的表达及其与氧化应激和疾病进展的相关性。然后，我们用过氧化氢处理结肠 HCT116 细胞以诱导氧化应激，并使用 TRAP1 抑制剂 gamitrinib-triphenylphosphonium（GTPP）抑制 TRAP1。我们在这种情况下使用液相色谱串联质谱（LC-MS/MS）检测细胞蛋白质组学图谱，并与对照组进行比较。我们还进一步研究了治疗对 DNA 损伤和细胞存活的影响。
氧化应激下的 TRAP1 表达与结直肠癌的疾病结局相关。氧化应激下的 TRAP1 抑制诱导了代谢重编程和热休克因子 1（HSF1）依赖性的转激活。此外，与单一治疗和非治疗对照组相比，我们还观察到在氧化应激和 TRAP1 抑制下，细胞中的 DNA 损伤和细胞死亡诱导增强。
这些发现为 TRAP1 驱动的代谢重编程对氧化应激的反应提供了新的见解。
