2014
DOI: 10.1186/s12915-014-0094-0
|View full text |Cite
|
Sign up to set email alerts
|

Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy

Abstract: Genomic alterations may make cancer cells more dependent than normal cells on mechanisms of proteostasis, including protein folding and degradation. This proposition is the basis for the clinical use of proteasome inhibitors to treat multiple myeloma and mantle cell lymphoma. However, proteasome inhibitors have not proved effective in treating other cancers, and this has called into question the general applicability of this approach. Here, I consider possible explanations for this apparently limited applicabi… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1

Citation Types

9
296
0
2

Year Published

2015
2015
2023
2023

Publication Types

Select...
8
2

Relationship

0
10

Authors

Journals

citations
Cited by 306 publications
(307 citation statements)
references
References 115 publications
(126 reference statements)
9
296
0
2
Order By: Relevance
“…Furthermore, mutations in protein-coding regions, frequent in cancer, also increase the load of aberrant proteins and the risk of proteotoxic stress; in that regard, it is remarkable that FGF13 overexpression is observed in lung cancer and melanoma, two cancer types harboring extensive somatic mutations. The challenge to proteostasis in tumor cells may be exacerbated further by the presence of DNA duplications, deletions, and copy number variations, causing imbalance in the stoichiometry of multisubunit complexes (51). We propose that FGF13 up-regulation dampens this proteostasis stress by tuning down the rate of protein synthesis, eventually bringing it to a level that represents a compromise between the need to produce more proteins and the ability of the cancer cell to evade lethal proteotoxic stress.…”
Section: Fgf13 Depletion Augments Nucleolar Size and Increases Rrna Andmentioning
confidence: 99%
“…Furthermore, mutations in protein-coding regions, frequent in cancer, also increase the load of aberrant proteins and the risk of proteotoxic stress; in that regard, it is remarkable that FGF13 overexpression is observed in lung cancer and melanoma, two cancer types harboring extensive somatic mutations. The challenge to proteostasis in tumor cells may be exacerbated further by the presence of DNA duplications, deletions, and copy number variations, causing imbalance in the stoichiometry of multisubunit complexes (51). We propose that FGF13 up-regulation dampens this proteostasis stress by tuning down the rate of protein synthesis, eventually bringing it to a level that represents a compromise between the need to produce more proteins and the ability of the cancer cell to evade lethal proteotoxic stress.…”
Section: Fgf13 Depletion Augments Nucleolar Size and Increases Rrna Andmentioning
confidence: 99%
“…Importantly, p97 has recently been recognized as a promising target of cancer chemotherapy [15]. Potent ATP-competitive and allosteric p97 inhibitors have been developed and are entering phase I clinical trials.…”
Section: Introductionmentioning
confidence: 99%
“…3 Functional p97 is hexameric, with each protomer consisting of three major domains that could be targeted to inhibit overall function. These domains include two highly conserved Walker A and B motif-containing ATPase domains (D1 and D2) and an N-terminal domain that interfaces with the D1 domain.…”
Section: Introductionmentioning
confidence: 99%