Byun, Hee Sun Ju, Eunjin Park, Kyeong Ah Sohn, Kyung-Cheol Jung, Chan Seok Hong, Jang Hee Ro, Hyunju Lee, Hoi Young Quan, Khong Trong Park, InWha Na, MinKyun Hur, Gang Min 2024-01-19T09:03:38Z 2024-01-19T09:03:38Z 2022-10-11 2023-08 0742-2091 https://pubs.kist.re.kr/handle/201004/113479 The activation of receptor-interacting protein kinase 1 (RIPK1) by death-inducing signaling complex (DISC) formation is essential for triggering the necroptotic mode of cell death under apoptosis-deficient conditions. Thus, targeting the induction of necroptosis by modulating RIPK1 activity could be an effective strategy to bypass apoptosis resistance in certain types of cancer. In this study, we screened a series of arborinane triterpenoids purified from Rubia philippinesis and identified rubiarbonol B (Ru？B) as a potent caspase-8 activator that induces DISC-mediated apoptosis in multiple types of cancer cells. However, in RIPK3-expressing human colorectal cancer (CRC) cells, the pharmacological or genetic inhibition of caspase-8 shifted the mode of cell death by Ru？B from apoptosis to necroptosis though upregulation of RIPK1 phosphorylation. Conversely, Ru？B-induced cell death was almost completely abrogated by RIPK1 deficiency. The enhanced RIPK1 phosphorylation and necroptosis triggered by Ru？B treatment occurred independently of tumor necrosis factor receptor signaling and was mediated by the production of reactive oxygen species via NADPH oxidase 1 in CRC cells. Thus, we propose Ru？B as a novel anticancer agent that activates RIPK1-dependent cell death via ROS production, and suggest its potential as a novel necroptosis-targeting compound in apoptosis-resistant CRC. English Kluwer Academic Publishers Rubiarbonol B induces RIPK1-dependent necroptosis via NOX1-derived ROS production Article 10.1007/s10565-022-09774-6 1 Cell Biology and Toxicology, v.39, no.4, pp.1677 - 1696 Cell Biology and Toxicology 39 4 1677 1696 N scie scopus 000859791700001 Cell Biology Toxicology Cell Biology Toxicology Article NF-KAPPA-B COLON-CANCER CELLS MEDIATED APOPTOSIS NADPH OXIDASES DEATH NECROSIS RECEPTOR NOX1 INDUCTION KINASE RIPK1 RIPK3 Rubiarbonol B Necrosome NOX1