Signaling alterations caused by drugs and autophagy.

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.

• Authors: Paul Dent, Laurence Booth, Andrew Poklepovic, John F Hancock
• Journal: Cellular signalling (Cell Signal) Vol. 64 Pg. 109416 (Dec 2019) ISSN: 1873-3913 [Electronic] England
• PMID: 31520735 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Histone Deacetylase Inhibitors
• Molecular Chaperones
• Protein Kinase Inhibitors
• Histone Deacetylases

Topics

• Autophagosomes (metabolism)
• Autophagy (drug effects)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Molecular Chaperones (metabolism)
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology)