The epichaperome: the power of many as the power of one

Wang, Tai; Guzmán, Mónica L.; Chiosis, Gabriela

doi:10.18632/oncoscience.321

Cited by 6 publications

(4 citation statements)

References 8 publications

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“…Oligomer formation can modulate ligand binding sites and thus alter affinity and specificity, increase the concentration of bound molecules, generate links between different cellular components and transmit signals, ions and other molecules across biological membranes 53,54 . More explicitly, oligomerization increases fitness and functionality, and components within the chaperome may assemble to acquire new competitive advantages and expand functional breadth 55 . Chaperome oligomerization to modulate function has been observed in bacteria, plants and other organisms in addition to human cells (BOX 3).…”

Section: The Hsp90-hsp70 Chaperomementioning

confidence: 99%

Adapting to stress — chaperome networks in cancer

et al. 2018

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In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

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Section: The Hsp90-hsp70 Chaperomementioning

confidence: 99%

Adapting to stress — chaperome networks in cancer

et al. 2018

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“…Heat shock proteins (Hsps) are a set of well-conserved, highly expressed molecular chaperones that are vital for cellular function (Freilich et al 2018;Kim et al 2013). Originally identified as proteins induced by thermal stress, it is now understood that Hsps play important roles in protecting cells against a range of cell stresses that include DNA damage, oxidative stress, metabolic challenges and aging (Freilich et al 2018;Kim et al 2013;Rodina et al 2016;Tai et al 2016). Heat shock protein 70 (Hsp70) and Heat shock protein 90 (Hsp90) are both imperative for the folding and stabilization of the majority of the proteome (Kim et al 2013;Li et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Novel insights into molecular chaperone regulation of ribonucleotide reductase

2018

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The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many disease related proteins including those in cancer. Substantial effort has been devoted to developing a range of chaperone inhibitors for clinical use. Recent studies have identified the oncogenic ribonucleotide reductase (RNR) complex as an interactor of chaperones. While several generations of RNR inhibitor have been developed for use in cancer patients, many of these produce severe side effects such as nausea, vomiting and hair loss. Development of more potent, less patient-toxic anti-RNR strategies would be highly desirable. Inhibition of chaperones and associated co-chaperone molecules in both cancer and model organisms such as budding yeast result in the destabilization of RNR subunits and a corresponding sensitization to RNR inhibitors. Going forward, this may form part of a novel strategy to target cancer cells that are resistant to standard RNR inhibitors.

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“…Extracellular HSP profiling may be of critical importance in oncology. During tumorigenesis for example, HSPs may form stable overlapping high affinity complexes that Chiosis has identified as the epichaperome (Tai et al 2016). Type 1 cancers with codependent chaperomes were identified as vulnerable to single HSP inhibitors as a central lethality regardless of tissue origin or stage.…”

Section: Discussionmentioning

confidence: 99%

A robust strategy for proteomic identification of biomarkers of invasive phenotype complexed with extracellular heat shock proteins

Griffiths¹,

Ezrin²,

Jackson

et al. 2019

Cell Stress and Chaperones

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As an extension of their orchestration of intracellular pathways, secretion of extracellular heat shock proteins (HSPs) is an emerging paradigm of homeostasis imperative to multicellular organization. Extracellular HSP is axiomatic to the survival of cells during tumorigenesis; proportional representation of specific HSP family members is indicative of invasive potential and prognosis. Further significance has been added by the knowledge that all cancer-derived exosomes have surface-exposed HSPs that reflect the membrane topology of cells that secrete them. Extracellular HSPs are also characteristic of chronic inflammation and sepsis. Accordingly, interrogation of extracellular HSPs secreted from cell culture models may represent a facile means of identifying translational biomarker signatures for targeting in situ. In the current study, we evaluated a simple peptide-based multivalent HSP affinity approach using the Vn96 peptide for low speed pelleting of HSP complexes from bioreactor cultures of cell lines with varying invasive phenotype in xenotransplant models: U87 (glioblastoma multiforme; invasive); HELA (choriocarcinoma; minimally invasive); HEK293T (virally transformed immortalized; embryonic). Proteomic profiling by bottom-up mass spectrometry revealed a comprehensive range of candidate biomarkers including primary HSP ligands. HSP complexes were associated with additional chaperones of prognostic significance such as protein disulfide isomerases, as well as pleiotropic metabolic enzymes, established as proportionally reflective of invasive phenotype. Biomarkers of inflammatory and mechanotransductive phenotype were restricted to the most invasive cell model U87, including chitinase CHI3L1, lamin C, amyloid derivatives, and histone isoforms.

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The epichaperome: the power of many as the power of one

Cited by 6 publications

References 8 publications

Adapting to stress — chaperome networks in cancer

Adapting to stress — chaperome networks in cancer

Novel insights into molecular chaperone regulation of ribonucleotide reductase

A robust strategy for proteomic identification of biomarkers of invasive phenotype complexed with extracellular heat shock proteins

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