TRAF3/p38-JNK Signalling Crosstalk with Intracellular-TRAIL/Caspase-10-Induced Apoptosis Accelerates ROS-Driven Cancer Cell-Specific Death by CD40.

IBRAHEEM, Khalidah, YHMED, Albashir MA, NASEF, Mohamed M and GEORGOPOULOS, Nikolaos (2022). TRAF3/p38-JNK Signalling Crosstalk with Intracellular-TRAIL/Caspase-10-Induced Apoptosis Accelerates ROS-Driven Cancer Cell-Specific Death by CD40. Cells, 11 (20): 3274.

Ibraheem_Cells paper_2022.pdf - Published Version
Creative Commons Attribution.

Download (3MB) | Preview
Official URL:
Link to published version::


The capacity to induce tumour-cell specific apoptosis represents the most unique feature of the TNF receptor (TNFR) family member CD40. Recent studies on the signalling events triggered by its membrane-presented ligand CD40L (mCD40L) in normal and malignant epithelial cells have started to unravel an exquisite context and cell type specificity for the functional effects of CD40. Here, we demonstrate that, in comparison to other carcinomas, mCD40L triggered strikingly more rapid apoptosis in colorectal carcinoma (CRC) cells, underpinned by its ability to entrain two concurrently operating signalling axes. CD40 ligation initially activates TNFR-associated factor 3 (TRAF3) and subsequently NADPH oxidase (NOX)/Apoptosis signal-regulating kinase 1 (ASK1)-signalling and induction of reactive oxygen species (ROS) to mediate p38/JNK- and ROS-dependent cell death. At that point, p38/JNK signalling directly activates the mitochondrial pathway, and triggers rapid induction of intracellular TNF-related apoptosis-inducing ligand (TRAIL) that signals from internal compartments to initiate extrinsic caspase-10-asscociated apoptosis, leading to truncated Bid (tBid)-activated mitochondrial signalling. p38 and JNK are essential both for direct mitochondrial apoptosis induction and the TRAIL/caspase-10/tBid pathway, but their involvement follows functional hierarchy and temporally controlled interplay, as p38 function is required for JNK phosphorylation. By engaging both intrinsic and extrinsic pathways to activate apoptosis via two signals simultaneously, CD40 can accelerate CRC cell death. Our findings further unravel the multi-faceted properties of the CD40/mCD40L dyad, highlighted by the novel TNFR crosstalk that accelerates tumour cell-specific death, and may have implications for the use of CD40 as a therapeutic target.

Item Type: Article
Uncontrolled Keywords: Humans; Colorectal Neoplasms; Reactive Oxygen Species; MAP Kinase Kinase Kinase 5; MAP Kinase Kinase 4; p38 Mitogen-Activated Protein Kinases; TNF Receptor-Associated Factor 3; CD40 Ligand; Apoptosis; BH3 Interacting Domain Death Agonist Protein; TNF-Related Apoptosis-Inducing Ligand; Caspase 10; CD40 Antigens; NADPH Oxidases; CD40; ROS; TNFR; TRAIL; apoptosis; carcinoma; receptor crosstalk; Humans; Apoptosis; Caspase 10; CD40 Antigens; CD40 Ligand; MAP Kinase Kinase Kinase 5; NADPH Oxidases; Reactive Oxygen Species; TNF Receptor-Associated Factor 3; TNF-Related Apoptosis-Inducing Ligand; p38 Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Colorectal Neoplasms; BH3 Interacting Domain Death Agonist Protein; 31 Biological sciences; 32 Biomedical and clinical sciences
Identification Number:
SWORD Depositor: Symplectic Elements
Depositing User: Symplectic Elements
Date Deposited: 22 Feb 2024 15:46
Last Modified: 22 Feb 2024 16:00

Actions (login required)

View Item View Item


Downloads per month over past year

View more statistics