The REV1-Targeting Inhibitor JH-RE-06 Triggers Programmed Cell Death by Regulating NCOA4-Mediated Ferritinophagy and the KEAP1-NRF2-ARE Pathway in CRC Cells
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Oncogenes accelerate DNA replication, triggering excessive replication origin activation. This leads to DNA replication stress and genomic instability in cancer cells, making replication stress a potential therapeutic target. Translesion synthesis (TLS) serves as a compensation mechanism for replication stress, enabling cancer cells to acquire a growth advantage. Cancer cells exploit translesion synthesis (TLS) to circumvent DNA adducts produced by platinum-based chemotherapeutics, leading to the emergence of resistance. Consequently, targeting TLS offers a dual advantage for oncological therapy. The application of the translesion synthesis polymerase REV1 inhibitor JH-RE-06 in the treatment of colorectal cancer (CRC) remains unexplored. The molecular mechanisms by which JH-RE-06 induces programmed cell death have also not been reported. Our findings revealed that JH-RE-06 could trigger programmed cell death in CRC cells.Specifically, JH-RE-06 enhances the level of cleaved caspase-3 and cleaved PARP1 in cancer cells, stimulates NCOA4-mediated ferritinophagy, which results in ferroptosis. Cells activate the KEAP1-NRF2 pathway in response to the oxidative stress caused by JH-RE-06. This programmed cell death (PCD) can be reversed by cysteine-synthesizing pharmaceuticals. While JH-RE-06 does not increase the sensitivity of CRC cells to oxaliplatin, it effectively suppresses clonal proliferation of oxaliplatin-resistant cell lines in vitro and inhibits oxaliplatin-resistant xenograft tumors growth in vivo . The data indicate that JH-RE-06 may serve as a viable second-line chemotherapeutic treatment for CRC in cases of chemoresistance.