Related Experiment Video
Updated: May 3, 2026
08:49
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
8.9K
Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies
Yuan-Feng Lin1, Tsung-Ching Lai, Chih-Kang Chang
1Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
The Journal of Clinical Investigation
|August 28, 2013
Summary
Targeting the XIAP:CASP7 interaction can kill cancer cells lacking Caspase-3 (CASP3/DR) and overcome drug resistance. This approach triggers apoptosis, offering a new strategy for treating aggressive malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Caspase-3 downregulation (CASP3/DR) in tumors leads to therapy resistance and poor prognosis.
- CASP3/DR cancer cells depend on caspase-7 (CASP7) for apoptosis, and XIAP inhibits activated CASP7 (p19/p12-CASP7).
Purpose of the Study:
- To identify a therapeutic target to overcome CASP3/DR-mediated resistance.
- To develop a protein-protein interaction (PPI) inhibitor for the XIAP:p19/p12-CASP7 complex.
Main Methods:
- Identified the Cys246 residue pocket on p19/p12-CASP7 as a target for PPI inhibition.
- Developed and tested a novel PPI inhibitor in vitro and in vivo.
- Investigated the role of microRNA let-7a-1 in mediating CASP3/DR.
Main Results:
- Inhibition of the XIAP:p19/p12-CASP7 PPI triggered CASP7-dependent apoptosis, selectively killing CASP3/DR tumors.
- Treatment showed no adverse effects on non-tumor cells.
- Targeting this PPI overcame multidrug resistance and resensitized cells to chemotherapy.
- CASP3/DR and p19/p12-CASP7 accumulation correlated with aggressive cancers and poor patient prognosis.
Conclusions:
- Targeting the XIAP:p19/p12-CASP7 complex offers a novel therapeutic strategy for CASP3/DR malignancies.
- This approach bypasses apical caspases and selectively eliminates resistant cancer cells.
- Findings elucidate the mechanism of CASP3/DR in cancer progression and resistance.
Related Concept Videos
02:57Targeted Cancer Therapies
7.0K
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...
There are several types of targeted therapies against...
7.0K
02:50Combination Therapies and Personalized Medicine
4.9K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.9K
01:24Caspases
8.7K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
8.7K
01:17The Extrinsic Apoptotic Pathway
6.2K
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...
6.2K
01:31The Intrinsic Apoptotic Pathway
6.2K
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...
6.2K
01:28CRISPR/Cas9 Genome Editing
3.2K
The CRISPR-Cas system serves as a bacterial defense mechanism against invading genetic elements such as viruses and plasmids, forming the foundation for its adaptation as a powerful genome-editing tool. Originally discovered in prokaryotes, this system has been repurposed to revolutionize genetic engineering across a wide range of organisms, including plants, animals, and humans. The core component, Cas9, is an endonuclease derived from Streptococcus pyogenes, capable of introducing...
3.2K