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Published on: February 16, 2015
New drugs, old fashioned ways: ER stress induced cell death
Pietro Di Fazio1, Matthias Ocker, Roberta Montalbano
1Institute for Surgical Research, Philipps University of Marburg, Baldingerstrasse, Marburg, Germany. difazio@med.uni-marburg.de
Abstract:
Discovery of small molecules able to induce several cellular self-killing mechanisms improved cancer therapy in the last years. Research focused on canonical apoptotic (mitochondria or death receptor related) pathways to induce cell death in several hematologic and solid malignancies, showing that treatment with different synthetic and natural compounds reactivates the cell death machinery previously silenced in resistant cancer cells. Besides the canonical apoptotic pathways, alternative pathways of cell death induction have recently been rediscovered as potential new targets for cancer therapy. Under certain conditions, protein folding can be disturbed causing an accumulation of unfolded proteins inside the endoplasmic reticulum (ER). This situation leads to stress ER, involving the transcriptional and translational machinery to induce the expression and post-transcriptional modifications of many factors involved in ER stress response mediated cell death. In this scenario, some apoptotic players like caspase 4 or caspase 12 start to control cell fate by inducing downstream cell death proteins. Recently, inhibitors of protein deacetylases have been demonstrated to potently induce this alternative cell death pathway and will be reviewed here.
Insights
Small molecules that trigger cell self-destruction are improving cancer treatments. Researchers are exploring alternative cell death pathways, like endoplasmic reticulum (ER) stress, as new therapeutic targets for resistant cancers.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Cancer therapy has advanced with small molecules inducing apoptosis (programmed cell death).
- Resistance in hematologic and solid malignancies often involves silenced cell death pathways.
- Alternative cell death mechanisms, distinct from canonical apoptosis, are emerging as novel therapeutic targets.
Purpose of the Study:
- To review the role of alternative cell death pathways in cancer therapy.
- To highlight endoplasmic reticulum (ER) stress-mediated cell death as a potential strategy.
- To discuss the impact of protein deacetylase inhibitors on these alternative pathways.
Main Methods:
- Review of recent scientific literature on cell death induction in cancer.
- Analysis of mechanisms underlying ER stress and its role in cell fate.
- Examination of the therapeutic potential of targeting ER stress and protein deacetylases.
Main Results:
- Canonical apoptotic pathways (mitochondria, death receptor) are targets for synthetic and natural compounds.
- Endoplasmic reticulum (ER) stress, caused by unfolded protein accumulation, triggers alternative cell death.
- Caspase 4 and caspase 12 are implicated in ER stress-mediated cell death.
- Inhibitors of protein deacetylases effectively induce this alternative cell death pathway.
Conclusions:
- Alternative cell death pathways, particularly ER stress, offer new avenues for cancer treatment.
- Targeting ER stress response and utilizing protein deacetylase inhibitors show promise for overcoming cancer resistance.
- Further research into these alternative pathways could lead to more effective cancer therapies.
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