Metabolic Targeting of NRF2 Potentiates the Efficacy of the TRAP1 Inhibitor G-TPP Through Reduction of ROS Detoxification in Colorectal Cancer

Authors

Hong-Yuan Tsai
Mary P Bronner
Jordon K March
John F Valentine
Noah F Shroyer
Lisa A Lai
Teresa A Brentnall
Sheng Pan
Ru Chen

Publication Date

11-28-2022

Journal

Cancer Letters

DOI

10.1016/j.canlet.2022.215915

PMID

36113636

PMCID

PMC11262000

PubMedCentral® Posted Date

7-22-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Antioxidants, Colonic Neoplasms, Colorectal Neoplasms, HSP90 Heat-Shock Proteins, Humans, Macrocyclic Compounds, NF-E2-Related Factor 2, Poly(ADP-ribose) Polymerase Inhibitors, Reactive Oxygen Species, Receptors, Tumor Necrosis Factor, Terphenyl Compounds, Colon cancer, ROS, TRAP1, CHOP, NRF2

Abstract

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.

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