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Published on: May 21, 2020
TAF15 contributes to the radiation-inducible stress response in cancer
Abhay Kumar Singh1, Vaishali Kapoor1, Dinesh Thotala1,2
1Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.
Abstract:
Resistance to radiation therapy is a significant problem in the treatment of non-small cell lung cancer (NSCLC). There is an unmet need to discover new molecular targets for drug development in combination with standard of care cancer therapy. We found that TAF15 was radiation-inducible using phage-displayed peptide libraries. In this study, we report that overexpression of TAF15 is correlated with worsened survival in NSCLC patients. Radiation treatment led to surface induction of TAF15 in vitro and in vivo. We genetically silenced TAF15 which led to a significant reduction in proliferation of NSCLC cells. Cells depleted of TAF15 exhibited cell cycle arrest and enhanced apoptosis through activation and accumulation of p53. In combination with radiation, TAF15 knockdown led to a significant reduction in the surviving fraction of NSCLC cell lines. To determine the importance of TAF15 surface expression, we targeted TAF15 with an antibody. In combination with radiation, the anti-TAF15 antibody led to a reduction in the surviving fraction of cancer cells. These studies show that TAF15 is a radiation-inducible molecular target that is accessible to anti-cancer antibodies and enhances cell viability in response to radiation.
Insights
TAF15 is a radiation-inducible protein that worsens survival in non-small cell lung cancer (NSCLC). Silencing TAF15 or targeting it with an antibody enhances radiation therapy effectiveness, offering new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Radiation resistance is a major challenge in non-small cell lung cancer (NSCLC) treatment.
- Novel molecular targets are needed for combination therapies.
- TAF15 was identified as a radiation-inducible protein.
Purpose of the Study:
- To investigate the role of TAF15 in NSCLC radiation resistance.
- To evaluate TAF15 as a therapeutic target for NSCLC.
Main Methods:
- Phage-displayed peptide libraries to identify radiation-inducible targets.
- Genetic silencing of TAF15 in NSCLC cells.
- In vitro and in vivo studies of TAF15 expression and function.
- Antibody-based targeting of surface-expressed TAF15.
Main Results:
- TAF15 overexpression correlates with poorer survival in NSCLC patients.
- Radiation induces TAF15 expression on the cell surface.
- TAF15 depletion causes cell cycle arrest, apoptosis, and reduced proliferation.
- Combined radiation and TAF15 knockdown significantly reduce cancer cell survival.
- Anti-TAF15 antibody treatment combined with radiation decreases cancer cell survival.
Conclusions:
- TAF15 is a radiation-inducible target that promotes NSCLC cell viability.
- Surface-expressed TAF15 is accessible to antibody-based therapies.
- Targeting TAF15 offers a promising strategy to overcome radiation resistance in NSCLC.
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