Related Experiment Video

Updated: May 25, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into

Hai-Tong Fang1, Bo Zhang, Xiao-Fen Pan

  • 1Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Proceedings of the National Academy of Sciences of the United States of America
|February 7, 2012
PubMed

Insights

Bortezomib induces cancer cell death by targeting the C-KIT receptor tyrosine kinase pathway, leading to the degradation of heat shock protein 90β and release of Apaf-1. This mechanism promotes apoptosis in certain leukemias and tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Bortezomib, a proteasome inhibitor, shows efficacy in multiple myeloma but has complex anti-cancer mechanisms.
  • The role of receptor tyrosine kinases in bortezomib-induced apoptosis is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of bortezomib-induced apoptosis in C-KIT-dependent cancer cells.
  • To investigate the role of C-KIT, Hsp90β, and Apaf-1 in bortezomib's anti-cancer effects.

Main Methods:

  • Investigated C-KIT endocytosis and lysosomal degradation in response to bortezomib.
  • Analyzed the interaction and phosphorylation status of C-KIT, Hsp90β, and Apaf-1.
  • Assessed the cleavage of AML1-ETO fusion proteins by caspase-3.
  • Evaluated bortezomib efficacy in a mouse model of AML1-ETO9a leukemia.

Main Results:

  • Bortezomib-induced apoptosis requires C-KIT endocytosis and lysosomal degradation, unlike imatinib.
  • C-KIT binds and phosphorylates Hsp90β, which sequesters Apaf-1.
  • Bortezomib dephosphorylates Hsp90β, releasing Apaf-1 and activating caspase-3.
  • Caspase-3 cleaves AML1-ETO fusion proteins, contributing to apoptosis. Bortezomib showed efficacy in AML1-ETO9a leukemia models.

Conclusions:

  • The C-KIT-Hsp90β-Apaf-1 cascade is crucial for cancer cells to evade apoptosis.
  • Bortezomib disrupts this cascade, promoting cancer cell death.
  • Further exploration of bortezomib's therapeutic potential in C-KIT-driven neoplasms is warranted.

Related Concept Videos

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...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

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...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
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...