Related Experiment Video

Updated: Jun 17, 2026

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
06:38

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

Published on: September 12, 2019

TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies

Bruno-Christian Koehler1, Toni Urbanik, Binje Vick

  • 1First Department of Medicine, Johannes Gutenberg-University Mainz, 55101 Mainz, Germany.

World Journal of Gastroenterology
|December 17, 2009
PubMed
Abstract

Insights

Combining chemotherapy and kinase inhibitors with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) therapy can overcome TRAIL resistance in hepatocellular carcinoma (HCC). Targeting antiapoptotic BCL-2 proteins further enhances TRAIL-induced apoptosis in HCC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Hepatocellular carcinoma (HCC) often exhibits resistance to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis.
  • The antiapoptotic BCL-2 proteins MCL-1 and BCL-x(L) are implicated in mediating this TRAIL resistance.
  • Understanding resistance mechanisms is crucial for developing effective HCC treatments.

Purpose of the Study:

  • To investigate strategies for overcoming TRAIL resistance in HCC.
  • To evaluate the efficacy of combining chemotherapeutic drugs and kinase inhibitors with TRAIL.
  • To assess the role of antiapoptotic BCL-2 proteins in TRAIL resistance and potential therapeutic targeting.

Main Methods:

  • Analysis of TRAIL receptor expression and BCL-2 protein levels (MCL-1, BCL-x(L)) in HCC cell lines using flow cytometry and Western blotting.
  • Knock-down of MCL-1 and BCL-x(L) via small interfering RNA (siRNA) transfection.
  • Treatment of HCC cells with TRAIL, agonistic TRAIL antibodies, chemotherapeutic drugs, and various kinase inhibitors, followed by apoptosis and cell viability assays.

Main Results:

  • HCC cell lines (Huh7, Hep-G2) expressed TRAIL-R1 and -R2 but showed limited apoptosis upon TRAIL or agonistic antibody treatment.
  • Co-administration of chemotherapeutic drugs (5-fluorouracil, doxorubicin) or kinase inhibitors (LY294002, AG1478, PD98059, rapamycin, Sorafenib) significantly reduced TRAIL resistance.
  • Knock-down of MCL-1 and BCL-x(L) enhanced TRAIL-induced apoptosis and sensitized HCC cells to kinase inhibition.

Conclusions:

  • Blockage of survival kinases, combined with chemotherapy, represents a promising approach to overcome TRAIL resistance in HCC.
  • Targeting antiapoptotic BCL-2 proteins (MCL-1, BCL-x(L)) is a viable strategy to sensitize HCC cells to TRAIL-based therapies.
  • These findings offer potential therapeutic avenues for improving HCC treatment outcomes.
Keywords:
(Mitogen-activated protein kinase)/(extracellular signal regulated kinase) kinase5-fluorouracilApoptosisBCL-xLDoxorubicinHepatocellular carcinomaMCL-1Phosphoinositol-3-kinaseSorafenibTumor necrosis factor-related apoptosis inducing ligandc-Jun N-terminal kinase

More Related Videos

A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma12:24

A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma

Published on: September 30, 2021

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma09:11

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

Published on: May 24, 2024

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...
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...
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
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...