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Published on: February 6, 2015
Utilization of the cellular stress response to sensitize cancer cells to TRAIL-mediated apoptosis
1Department of Pathology & Cell Biology, Columbia University College of Physicians & Surgeons, 630 W. 168th Street, VC14-239, New York, NY 10032, USA. ms4169@columbia.edu
Introduction:
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising death ligand who has received significant attention due to its specific anti-cancer activity. Recently, a number of clinical trials involving either recombinant soluble TRAIL or agonistic death receptor (DR) antibodies have even been initiated. One major caveat in TRAIL-based anti-cancer therapies is that a considerable number of cancer cells are notorious resistant to apoptosis induction by TRAIL. Overcoming this primary or secondary evolved resistance is an utmost important goal of present cancer research. The current literature suggests that TRAIL resistance is mediated by a number of endogenous factors.
Areas Covered:
According to recent research, stress-related transcription factors have acquired a pivotal role in the sensitization of highly resistant cancer cells, for example, pancreatic cancer and glioblastoma cells, to TRAIL-mediated cell death. Out of this transcription factor family, C/EBP-homologous protein (CHOP) is linked to the control of DR-mediated apoptosis by modulation of several apoptotic and anti-apoptotic factors. Stress responses in certain organelles, such as endoplasmic reticulum (ER) and mitochondria, are potent inductors of CHOP expression. This report focuses on the influence of stress responses on endogenous or acquired resistance to extrinsic apoptosis in tumor cells and summarizes recent findings and results. The Medline and ClinicalTrials database with key words were used for this review.
Expert Opinion:
A potential novel treatment strategy for highly treatment-resistant tumors is the induction of a cellular stress response in cancer cells. The induction of an organelle-related stress response, such as nuclear, ER and mitochondrial stress, leads to a dramatic sensitization of a broad variety of cancer cells of different tumor entities to the apoptotic ligand, TRAIL. Importantly, non-neoplastic cells are not sensitized to TRAIL-mediated cell death through the unfolded protein response in most instances, suggesting that this treatment is not only of high efficacy, but even more less of unwanted toxicity in patients.
Insights
Inducing cellular stress responses can sensitize resistant cancer cells to TRAIL therapy. This approach targets organelle stress, enhancing apoptosis and potentially reducing toxicity in patients.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy but faces resistance.
- Overcoming TRAIL resistance in cancer cells is a critical research goal.
- Endogenous factors are implicated in mediating TRAIL resistance.
Purpose of the Study:
- To explore the role of cellular stress responses in overcoming TRAIL resistance.
- To investigate how organelle stress influences cancer cell sensitization to TRAIL.
- To review recent findings on stress responses and TRAIL-mediated apoptosis.
Main Methods:
- Literature review using Medline and ClinicalTrials databases.
- Focus on stress-related transcription factors, particularly C/EBP-homologous protein (CHOP).
- Analysis of stress responses in organelles like the endoplasmic reticulum (ER) and mitochondria.
Main Results:
- Stress-related transcription factors, like CHOP, play a key role in sensitizing resistant cancer cells (e.g., pancreatic, glioblastoma) to TRAIL.
- Organelle stress (nuclear, ER, mitochondrial) induces CHOP expression and modulates apoptosis.
- Cancer cells with induced stress responses show increased sensitization to TRAIL.
Conclusions:
- Inducing cellular stress responses presents a novel strategy for treating resistant tumors.
- Organelle stress significantly sensitizes diverse cancer cells to TRAIL, enhancing apoptosis.
- This approach demonstrates high efficacy with potentially reduced toxicity, as non-cancerous cells are less affected.
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