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

Abstract

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.

Identifying differentially expressed genes in goat mammary epithelial cells induced by overexpression of SOCS3 gene using RNA sequencing

“…MMP13 contributes to the proliferation, migration, and anchorage-independent clonogenicity of mouse mammary tumorigenic cell lines ( 29 ). The tumor necrosis factor receptor family member CD40 is critical for the immune system and induces tumor cell-specific apoptosis ( 30 ). However, how the regulation of BCL2 , MMP11 , MMP13 , and CD40 mediated by SOCS3 overexpression affects lipid metabolism and the complex relationship between cell survival and lipid metabolism remains unclear.…”

A novel method for the establishment of autologous skin cell suspensions: characterisation of cellular sub-populations, epidermal stem cell content and wound response-enhancing biological properties

“…Cells were then rinsed twice in PBS +1% FBS buffer. For surface protein expression, immunolabelled cells were acquired on a Guava EasyCyte 5 flow cytometer and data analyzed using EasyCyte software (Millipore, Watford, United Kingdom) as previously (Ibraheem et al, 2022).…”

“…Quantitative protein detection was performed by immunoblotting as detailed elsewhere (Ibraheem et al, 2022). Briefly, cell cultures were lysed and lysates established using an SDS-based buffer (Georgopoulos et al, 2014) containing 2 mg/mL DTT and 1% (v/v) protease inhibitor cocktail set 3 (Calbiochem, supplied my Merck).…”

JNK Cascade-Induced Apoptosis—A Unique Role in GqPCR Signaling

“…Although this phosphorylation protects Bid from cleavage by caspase-8, it allows a more profound cleavage of Bid to jBid to promote apoptosis. Furthermore, JNK can also induce TRAIL to initiate either caspase-10-associated, or tBid-activated mitochondrialinduced apoptosis [115]. Furthermore, it was shown that JNK can translocate to the mitochondria in response to TNF, where it interacts with Sh3BP5 at the mitochondrial membrane [116].…”