Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine

Siraj Pallichankandy; Faisal Thayyullathil; Anees Rahman Cheratta; Karthikeyan Subburayan; Ameer Alakkal; Mehar Sultana; Nizar Drou; Muhammad Arshad; Saeed Tariq; Sehamuddin Galadari

doi:10.1038/s41420-023-01376-3

Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine

Cell Death Discov. 2023 Mar 13;9(1):94. doi: 10.1038/s41420-023-01376-3.

Affiliations

¹ Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE.
² Center for Genomics and Systems Biology (CGSB), New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE.
³ Bioinformatics Core, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE.
⁴ Department of Anatomy, College of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain, UAE.
⁵ Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE. sehamuddin@nyu.edu.

Abstract

Oxeiptosis is a recently identified reactive oxygen species (ROS)-sensitive, caspase independent, non-inflammatory regulated cell death pathway. The activation of Kelch-like ECH-associated protein 1-Phosphoglycerate mutase 5-Apoptosis inducing factor mitochondria associated 1 (KEAP1-PGAM5-AIFM1) pathway is the key signaling event in the execution of oxeiptosis. In the present study, we demonstrate that sanguinarine (SNG), a quaternary benzophenanthridine alkaloid, induces oxeiptosis in human colorectal cancer (CRC) cells via ROS, specifically hydrogen peroxide (H₂O₂)-dependent activation of KEAP1-PGAM5-AIFM1 signaling axis. Whilst, knockdown of KEAP1, PGAM5, and AIFM1 largely abolishes SNG-induced oxeiptosis, hence reinforcing the importance of the role of this pathway in the SNG-mediated cytotoxicity. Moreover, extracellular addition of H₂O₂ sensitizes SNG-induced oxeiptosis in CRC cells, while removal of intracellular ROS by ROS scavengers, not only alleviated the overproduction of ROS caused by SNG, but also reversed the biochemical events associated with oxeiptosis. Finally, in vivo study demonstrates that SNG effectively reduces the tumor growth in HT-29 xenograft mouse model through features associated with oxeiptosis. This study highlights oxeiptosis as a novel tumor suppressive mechanism and further investigation of the role of oxeiptosis in cancer treatment is warranted.