TNFalpha potentiates 2-methoxyestradiol-induced mitochondrial death pathway

Mojgan Djavaheri-Mergny1, Juana Wietzerbin, Dany Rouillard

  • 1INSERM U365, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. Mergny@vjf.inserm.fr

Insights

Ewing sarcoma cells resistant to TNFalpha-induced death can be killed by combining TNFalpha with 2-Me. This combination therapy targets mitochondrial cell death pathways, offering a potential new treatment for Ewing tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Ewing sarcoma cells exhibit resistance to tumor necrosis factor-alpha (TNFalpha)-induced cell death.
  • This resistance is attributed to the activation of the transcription factor nuclear factor-kappa B (NF-kappaB).

Purpose of the Study:

  • To investigate if NF-kappaB activation affects 2-Me-induced cell death signaling in Ewing sarcoma.
  • To evaluate the combined effect of 2-Me and TNFalpha on Ewing sarcoma cells.

Main Methods:

  • Treatment of Ewing sarcoma cells with 2-Me alone and in combination with TNFalpha.
  • Analysis of cell death signaling pathways, focusing on mitochondrial pathways.

Main Results:

  • TNFalpha and 2-Me synergistically induce apoptosis in Ewing sarcoma cells.
  • The combination therapy activates mitochondrial cell death signaling pathways.

Conclusions:

  • NF-kappaB activation may not completely inhibit 2-Me-induced cell death when combined with TNFalpha.
  • Combined treatment with TNFalpha and 2-Me shows promise as a therapeutic strategy for Ewing tumors.

Related Concept Videos

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...
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...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.