Related Experiment Video

Updated: Aug 14, 2026

Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation
07:17

Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation

Published on: August 23, 2024

TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies

Marion MacFarlane1, Susan L Kohlhaas, Michael J Sutcliffe

  • 1Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, UK.

Cancer Research
|December 17, 2005
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy requires understanding cancer cell signaling. Chronic lymphocytic leukemia and mantle cell lymphoma cells primarily signal apoptosis via TRAIL-R1, not TRAIL-R2, impacting treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies are investigated for cancer therapy.
  • TRAIL induces apoptosis by activating either TRAIL-R1 or TRAIL-R2.
  • Previous studies suggested chronic lymphocytic leukemia (CLL) cells signal apoptosis mainly through TRAIL-R1.

Purpose of the Study:

  • To synthesize TRAIL mutants selective for TRAIL-R1 or TRAIL-R2.
  • To unequivocally determine the primary apoptotic signaling pathway in primary CLL and mantle cell lymphoma (MCL) cells.
  • To inform the optimization of TRAIL-based cancer therapies.

Main Methods:

  • Synthesis of mutant forms of TRAIL with specificity for TRAIL-R1 or TRAIL-R2.
  • Assessment of apoptosis induction in cell lines and primary patient cells using TRAIL mutants.
  • Analysis of receptor binding and death-inducing signaling complex formation.

Main Results:

  • TRAIL mutants demonstrated selective binding and apoptosis induction via cognate receptors.
  • Primary CLL and MCL cells were shown to signal apoptosis almost exclusively through TRAIL-R1.
  • Agents signaling predominantly through TRAIL-R2 are unlikely to benefit these specific patient groups.

Conclusions:

  • Apoptotic signaling in CLL and MCL is predominantly mediated by TRAIL-R1.
  • Therapeutic strategies using TRAIL agonists must consider the specific receptor utilized by tumor cells.
  • Determining TRAIL-R1 or TRAIL-R2 dependency is crucial for rational TRAIL therapy optimization.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...