Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

Molineaux, Susan M.

doi:10.1158/1078-0432.ccr-11-0853

Cited by 49 publications

(35 citation statements)

References 62 publications

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“…A second generation of proteasome inhibitors, including NPI-0052 (salinosporamide A), PR-171 (carfilzomib), and MLN9708, are now entering the clinic. Efficacy has also been reported for proteasome inhibitors in combination with other cytotoxic agents and targeted therapies such as histone deacetylase inhibitors and HSP90 inhibitors (78,82). Several proteins central to MCL, including cyclin D1, CDK4, AKT, and p53, bind to the molecular chaperone HSP90, suggesting that HSP90 inhibitors may be a suitable therapeutic target (83).…”

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 97%

“…Proteasome inhibitors disrupt the ubiquitin-proteasome system (78). Bortezomib induces apoptosis in MCL through upregulation of the BH3-only protein NOXA (79).…”

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 99%

“…Several proteins central to MCL, including cyclin D1, CDK4, AKT, and p53, bind to the molecular chaperone HSP90, suggesting that HSP90 inhibitors may be a suitable therapeutic target (83). However, HSP90 inhibitors as well as histone deacetylase inhibitors have demonstrated only moderate clinical antitumor activity when used alone (78,82,84). mTOR is another attractive target for new therapies (85).…”

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 99%

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Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 97%

“…Proteasome inhibitors disrupt the ubiquitin-proteasome system (78). Bortezomib induces apoptosis in MCL through upregulation of the BH3-only protein NOXA (79).…”

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 99%

Section: Target Therapy In Mcl: a Promise Of More Successful Treatmentsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

View full text Add to dashboard Cite

show abstract

“…The potential success of this approach in the treatment of cancer was first highlighted by the proteasome inhibitor, bortezomib, which has developed into an important treatment for multiple myeloma and mantle cell lymphoma (328). The proteasome features three dominant proteolytic activities, the trypsin-like, the chymotrypsin-like, and the peptidyl-glutamyl-peptide-cleaving (acidic) activity.…”

Section: Implications For Drug Designmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…In support of such an approach, bortezomib is already approved in multiple myeloma, and further proteasome inhibitors are in development. 34,35 Furthermore, combinations of bortezomib with HSP90 inhibitors are showing clinical promise in multiple myeloma, a cancer in which buffering of proteotoxic stress is especially critical for survival. 1,5 A further important aspect brought to light by genome-wide surveys is the extensive functional diversity of proteins affected by HSP90 inhibition.…”

Section: Expanding the Hsp90 Proteome Using Silac Technologymentioning

confidence: 99%

The expanding proteome of the molecular chaperone HSP90

2012

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T he molecular chaperone HSP90 maintains the activity and stability of a diverse set of "client" proteins that play key roles in normal and disease biology. Around 20 HSP90 inhibitors that deplete the oncogenic clientele have entered clinical trials for cancer. However, the full extent of the HSP90-dependent proteome, which encompasses not only clients but also proteins modulated by downstream transcriptional responses, is still incompletely characterized and poorly understood. Earlier large-scale efforts to define the HSP90 proteome have been valuable but are incomplete because of limited technical sensitivity. Here, we discuss previous large-scale surveys of proteome perturbations induced by HSP90 inhibitors in light of a significant new study using state-of-the-art stable isotope labeling by amino acids (SILAC) technology combined with more sensitive highresolution mass spectrometry (MS) that extends the catalog of proteomic changes in inhibitor-treated cancer cells. Among wide-ranging changes, major functional responses include downregulation of protein kinase activity and the DNA damage response alongside upregulation of the protein degradation machinery. Despite this improved proteomic coverage, there was surprisingly little overlap with previous studies. This may be due in part to technical issues but is likely also due to the variability of the HSP90 proteome with the inhibitor conditions used, the cancer cell type and the genetic status of client proteins. We suggest future proteomic studies to address these factors, to help distinguish client protein components from indirect transcriptional

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Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

Cited by 49 publications

References 62 publications

Molecular pathogenesis of mantle cell lymphoma

Molecular pathogenesis of mantle cell lymphoma

Degrons in cancer

The expanding proteome of the molecular chaperone HSP90

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