Proteotoxic Stress and Cell Death in Cancer Cells

Abstract

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact on normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed to restore proteostasis, allowing cells to survival the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress and this condition could be exploited in a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

Enhancing Proteotoxic Stress in Leiomyosarcoma Cells Triggers Mitochondrial Dysfunctions, Cell Death, and Antitumor Activity in vivo

“…Cell death in leiomyosarcoma cells is characterized by the upregulation of the BH3-only protein NOXA/PMAIP1 (Fig. 2C), a component of the apoptotic pathway elicited by endoplasmic reticulum stress (12). The induction of caspase activity by 2c is verified by the proteolytic processing of death substrate HDAC4 (27).…”

“…Induction of proteotoxic stress can be observed in relation to genomic alterations (10,11,12). The overexpression of genes, as well as the accumulation of mutations in coding regions, can alter the normal proteostasis (12,30). These mutations would produce protein variants that are prone to misfolding, degradation, and aggregation.…”

“…They are also more exposed to reactive oxygen species (ROS) and starvation, which can cause protein misfolding (8,10). Aneuploidy, copy-number alterations, and the accumulation of point mutations in coding sequences are additional sources of proteotoxic stress (10)(11)(12). Cancer cells coexist with an increased level of proteotoxic stress by upregulating mechanisms counteracting protein misfolding including chaperones, the ubiquitin-proteasome system, and macroautophagy.…”

Transcriptional lockdown during acute proteotoxic stress

“…Both SITA and translational downregulation likely provide a survival benefit to stressed cells, possibly by sparing proteostasis capacity due to downregulated transcription and translation, respectively [ 7 , 16 , 40 ]. Neurodegeneration, cancer, and aging represent human conditions in which cells show signs of proteotoxic damage [ 65. , 66.…”

Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy

“…The increased load of misfolded proteins in malignant cells as well as their altered metabolic state generates a therapeutic window at which limiting the activity of these proteolytic systems has lethal consequences for cancer cells without causing substantial collateral damage to healthy, untransformed cells. Hence, in the face of constitutive proteotoxic stress, curtailing the destruction of misfolded proteins in malignant cells causes uncontrolled accumulation of aberrant proteins that pollute their intracellular environment, resulting in induction of cell death due to an unresolvable loss of proteostasis [ 16 ].…”