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ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

100%

Swann Matassa D., Arzeni D., Landriscina M., Esposito F.

Endoplasmic Reticulum Stress in Diseases

2014

vol. 1

issue 1

TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles’ homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.

Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis

63%

Grek C., Townsend D. M.

Endoplasmic Reticulum Stress in Diseases

2014

vol. 1

issue 1

Cellular homeostasis requires the balance of a multitude of signaling cascades that are contingent upon the essential proteins being properly synthesized, folded and delivered to appropriate subcellular locations. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. The integrity of protein folding is enabled by the presence of ATP, Ca++, molecular chaperones, as well as an oxidizing redox environment. The imbalance between the load and capacity of protein folding results in a cellular condition known as ER stress. Failure of these pathways to restore ER homeostasis results in the activation of apoptotic pathways. Protein disulfide isomerases (PDI) compose a superfamily of oxidoreductases that have diverse sequences and are localized in the ER, nucleus, cytosol, mitochondria and cell membrane. The PDI superfamily has multiple functions including, acting as molecular chaperones, protein-binding partners, and hormone reservoirs. Recently , PDI family members have been implicated in the regulation of apoptotic signaling events. The complexities underlying the molecular mechanisms that define the switch from pro-survival to pro-death response are evidenced by recent studies that reveal the roles of specific chaperone proteins as integration points in signaling pathways that determine cell fate. The following review discusses the dual role of PDI in cell death and survival during ER stress.

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2 Endoplasmic Reticulum Stress in Diseases

2 2014

1 Arzeni D.

1 Esposito F.

1 Grek C.

1 Landriscina M.

1 Swann Matassa D.

1 Townsend D. M.

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ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis