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Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
Signaling alterations caused by drugs and autophagy
Paul Dent1, Laurence Booth1, Andrew Poklepovic2
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract:
Autophagy is an evolutionary conserved process that recycles cellular materials in times of nutrient restriction to maintain viability. In cancer therapeutics, the role of autophagy in response to multi-kinase inhibitors, alone or when combined with histone deacetylase (HDAC) inhibitors acts, generally, to facilitate the killing of tumor cells. Furthermore, the formation of autophagosomes and subsequent degradation of their contents can reduce the expression of HDAC proteins themselves as well as of other signaling regulatory molecules such as protein chaperones and mutated RAS proteins. Reduced levels of HDAC6 causes the acetylation and inactivation of heat shock protein 90, and, together with reduced expression of the chaperones HSP70 and GRP78, generates a strong endoplasmic reticulum (ER) stress response. Prolonged intense ER stress signaling causes tumor cell death. Reduced expression of HDACs 1, 2 and 3 causes the levels of programed death ligand 1 (PD-L1) to decline and the expression of Class I MHCA to increase which correlates with elevated immunogenicity of the tumor cells in vivo. This review will specifically focus on the downstream implications that result from autophagic-degradation of HDACs, RAS and protein chaperones.
Insights
Autophagy aids cancer therapy by degrading proteins like HDACs and RAS. This process enhances tumor cell death through ER stress and boosts immune response by reducing PD-L1.
Area of Science:
- Cellular Biology
- Cancer Research
- Molecular Oncology
Background:
- Autophagy is a cellular recycling process crucial for survival during nutrient deprivation.
- In cancer, autophagy often supports tumor cell survival but can be exploited therapeutically.
- Histone deacetylase (HDAC) inhibitors are emerging cancer therapeutics.
Purpose of the Study:
- To review the downstream effects of autophagy-mediated degradation of HDACs, RAS, and protein chaperones in cancer.
- To elucidate how this degradation impacts tumor cell viability and immunogenicity.
- To highlight the therapeutic implications of modulating autophagy in cancer treatment.
Main Methods:
- Literature review focusing on the interplay between autophagy and cancer therapeutics.
- Analysis of molecular mechanisms involving HDACs, protein chaperones (HSP70, GRP78), RAS, and endoplasmic reticulum (ER) stress.
- Examination of the impact on tumor immunogenicity, including PD-L1 and MHC Class I expression.
Main Results:
- Autophagic degradation reduces HDACs, leading to inactivation of HSP90 via acetylation and ER stress.
- Reduced expression of HDACs 1, 2, and 3 lowers PD-L1 and increases MHC Class I, enhancing anti-tumor immunity.
- Degradation of mutated RAS proteins and chaperones contributes to tumor cell death pathways.
Conclusions:
- Autophagy plays a dual role in cancer, but its role in degrading key proteins can be therapeutically exploited.
- Targeting autophagy can induce ER stress and enhance anti-tumor immune responses.
- Modulating autophagy offers a promising strategy for combination cancer therapy.
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