Related Experiment Video

Updated: Jul 4, 2026

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
10:06

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes

Lulzim Shkreta1, Ulrike Froehlich, Eric R Paquet

  • 1Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, Quebec, Canada.

Molecular Cancer Therapeutics
|June 21, 2008
PubMed

Insights

Many anticancer drugs alter gene splicing, promoting apoptosis by shifting the balance towards the pro-apoptotic Bcl-x(S) variant. This effect occurs through signaling pathways and varies significantly across different cancer cell lines.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Chemotherapy aims to induce apoptosis in cancer cells.
  • The impact of chemotherapy on alternative splicing of apoptotic genes remains largely unexplored.
  • Alternative splicing of Bcl-x (Bcl-xL/Bcl-xS) is crucial in regulating apoptosis.

Purpose of the Study:

  • To investigate the effect of mainstream anticancer drugs on the alternative splicing of apoptotic genes, specifically Bcl-x.
  • To determine if these drugs modulate splicing through signaling pathways or protein synthesis.
  • To assess drug-induced splicing changes in various cancer cell lines and identify cell line-specific responses.

Main Methods:

  • Testing 20 mainstream anticancer drugs for their ability to influence Bcl-x splice isoform production in 293 cells.
  • Investigating the role of de novo protein synthesis and caspase activity in drug-modulated splicing.
  • Analyzing the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes across multiple cancer cell lines (MCF-7, HeLa, PC-3, PA-1, SKOV-3).

Main Results:

  • Many tested drugs shifted Bcl-x splicing towards the pro-apoptotic Bcl-x(S) variant in 293 cells.
  • The observed splicing switch was independent of de novo protein synthesis and caspase activity, suggesting modulation via signaling events.
  • Several drugs also altered Bcl-x splicing in cancer cell lines, but the active drug set differed among cell lines.
  • Nearly all drugs affected alternative splicing of other apoptotic genes in a cell line-specific manner.
  • Drugs within the same class often targeted similar splicing events within a specific cell line, but these targets varied considerably between cell lines.

Conclusions:

  • Anticancer drugs can significantly influence alternative splicing of apoptotic genes, including Bcl-x.
  • Drug-induced splicing modulation likely occurs through cellular signaling pathways.
  • Significant cell line-specific differences exist in the response of apoptotic gene splicing to anticancer agents, highlighting the complexity of chemoresistance and drug efficacy.

More Related Videos

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition11:48

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Published on: October 9, 2014

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models09:58

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models

Published on: December 9, 2016

Related Concept Videos

RNA Splicing01:32

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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...
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...
Alternative RNA Splicing02:18

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
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...
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...