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Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-κB signaling pathway.

ABSTRACT: IL-17 A is a promoter of colorectal cancer initiation and progression. Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants, which has potent anti-inflammatory and antitumor actions. The effects of narciclasine on colorectal tumors were evaluated, with a focus on IL-17 A. Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts. The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis, findings confirmed by western blotting results of reduced Bcl-2 and enhanced Bax expression, as well as accumulation of cleaved Caspase-3, Caspase-8, Caspase-9, and cytoplasmic Cytochrome-c. After narciclasine incubation, IL-17 A, Act1, and TRAF6 were down-regulated, while p-P65 (Ser536) accumulated in the cytoplasm, a finding confirmed by laser scanning confocal microscopy. IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing. Moreover, IL-17 A, Act1, and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis. This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-κB anti-apoptotic signaling pathway.

SUBMITTER: Deng H

PROVIDER: S-EPMC11282404 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-κB signaling pathway.

Deng Huiming H Liu Qiang Q Yu Siman S Zhong Lifan L Gan Lianfang L Gu Huiquan H Wang Qianru Q Cheng Ruxin R Liu Yong Y Liu Li L Huang Ling L Xu Ronghua R

Genes & diseases 20230413 5

IL-17 A is a promoter of colorectal cancer initiation and progression. Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants, which has potent anti-inflammatory and antitumor actions. The effects of narciclasine on colorectal tumors were evaluated, with a focus on IL-17 A. Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts. The results of flow cytometry on JC-1 and Annexin V/PI revealed ...[more]

PMID: 39071112

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Project description:Background and purposeHyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell-cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI.MethodsMice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy. The expression of pro-inflammatory cytokine, including IL-6, TGF-β1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia.ResultsMice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-β1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively.ConclusionsIL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process. Video Abstract.

Dataset Information

Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-κB signaling pathway.

Publications

Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-κB signaling pathway.

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