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Oxidative Stress and the Proteasome: Mechanisms and Therapeutic Relevance

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

The proteasome is a key mediator of the oxidative environment in cells. Reactive oxygen species (ROS) are produced by normal cellular metabolic processes, and the proteasome can mediate ROS levels by degrading proteins that generate ROS and by controlling antioxidant turnover, as well as by clearing oxidatively damaged proteins from cells. The proteasome itself is also regulated by ROS, with certain subunits being susceptible to oxidative modification and damage, while other subunits are transcriptionally up-regulated as part of the antioxidant response. Proteasome inhibition has been shown to increase ROS in many cellular contexts, and this increase in ROS is often integral to cell death induction. Cells that have elevated basal levels of antioxidants, or that can mount a quick antioxidant response that often includes increasing proteasome subunit levels, can neutralize ROS and escape proteasome inhibitor-induced death. Many current studies are focused on overcoming this resistance by combining proteasome inhibitors with other ROS-generating agents, such as histone deacetylase inhibitors and certain kinase inhibitors, which can cause synergistic ROS induction and death.

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Abbreviations

AML:

Acute myeloid leukemia

ARE:

Antioxidant responsive element

ASK1:

Apoptosis signal-related kinase 1

(-)-EGCG:

(-)-Epigallocatechin gallate

GSH:

Glutathione

GSSG:

Glutathione disulfide

F1:

Ferritin

H2O2:

Hydrogen peroxide

HDACi:

Histone deacetylase inhibitor

HO–:

Hydroxyl radical

HO-1:

Heme oxygenase-1

IκBα:

NF-κB inhibitor α

IRE:

Iron responsive element

IRP2:

Iron regulatory protein 2

MEFs:

Mouse embryonic fibroblasts

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

NAC:

N-acetyl cysteine

NF-κB:

Nuclear factor-κB

Nox:

NADPH oxidase

Nrf2:

Nuclear factor-like 2

O2–:

Superoxide

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SOD2:

Superoxide dismutase 2

TNF-α:

Tumor necrosis factor-α

Trx:

Thioredoxin

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  1. Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 515 Holcombe Boulevard, Unit 0853, Houston, TX, 77030, USA

    Christa Manton & Joya Chandra Ph.D.

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  1. Christa Manton
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  2. Joya Chandra Ph.D.
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Correspondence to Joya Chandra Ph.D. .

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Manton, C., Chandra, J. (2014). Oxidative Stress and the Proteasome: Mechanisms and Therapeutic Relevance. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_10

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