Ras Chaperones

Kloog, Yoel; Elad-Sfadia, Galit; Haklai, Roni; Mor, Adam

doi:10.1016/b978-0-12-416749-0.00012-9

Cited by 7 publications

(3 citation statements)

References 98 publications

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“…Salirasib, also known as farnesylthiosalicylic acid (FTS), resembles the S -farnesylated cysteine on Ras (94,95) and is proposed to compete with it for binding to chaperones such as galectins (52,56,96). A small clinical trial showed that salirasib was well tolerated in pancreatic cancer patients (97), yet definitive answers as to whether it effectively perturbed KRAS function in patients, and can provide clinical benefit, remain to be determined.…”

Section: Targeting Ras Trafficking By Disrupting Ras-chaperone Interamentioning

confidence: 99%

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox

Der

Philips

2015

Clinical Cancer Research

320

292

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RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.

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Section: Targeting Ras Trafficking By Disrupting Ras-chaperone Interamentioning

confidence: 99%

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox

Der

Philips

2015

Clinical Cancer Research

320

292

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“…Consequently, the potential of ICMT as a therapeutic target encouraged the identification of inhibitors. Isoprenylated cysteine analogs inhibited ICMT activity and showed antiproliferative effects, however, their mechanism of action is not clear since some of them act as modulators of RAS chaperones (107,108). Indole-based molecules were also proposed, such as Cysmethynil (109), a competitive inhibitor with respect to isoprenylated cysteine and a non-competitive inhibitor with respect to SAM, which showed antitumor activity in vitro and in vivo (10,110,111).…”

Section: Discussionmentioning

confidence: 99%

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

et al. 2020

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Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.

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“…For example, the effect of the Ras inhibitor, S -trans, trans-farnesylthiosalicylic acid (FTS, Salirasib ® ), is mediated by targeting Ras chaperones that serve as key coordinators for proper Ras folding and delivery. This drug has been successfully evaluated in clinical trials of cancer patients [39]. In addition, targeting HSP90 with 17- N -allylamino-17-demethoxygeldanamycin sensitizes glioblastoma to celastrol treatment [40].…”

Section: Classical Proteostasis Network In Cancermentioning

confidence: 99%

The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

Dong

Cui

2018

Cells

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In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer’s disease. Enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development.

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Ras Chaperones

Cited by 7 publications

References 98 publications

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

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