Hsp90 Activity Modulation by Plant Secondary Metabolites
Total Page：16
File Type：pdf, Size：1020Kb
Reviews 1223 Hsp90 Activity Modulation by Plant Secondary Metabolites Authors Fabrizio Dal Piaz1, Stefania Terracciano 1, Nunziatina De Tommasi 1, Alessandra Braca 2 Affiliations 1 Dipartimento di Farmacia, Università di Salerno, Fisciano (SA), Italy 2 Dipartimento di Farmacia, Università di Pisa, Pisa, Italy Key words Abstract Abbreviations l" Hsp90 ! ! l" Hsp90 inhibitors Hsp90 is an evolutionarily conserved adenosine 17-AAG: 17-allylamino-17- l" plant molecules triphosphate-dependent molecular chaperone demethoxygeldanamycin l" client proteins and is one of the most abundant proteins in the AhR: aryl hydrocarbon receptor cells (1–3%). Hsp90 is induced when a cell under- Akt: protein kinase B goes various types of environmental stresses such BBM: berbamine as heat, cold, or oxygen deprivation. It is involved CEP: cepharanthine in the turnover, trafficking, and activity of client CL: celastrol proteins, including apoptotic factors, protein ki- 17-DMAG: 17-dimethylaminoethylamino-17- nases, transcription factors, signaling proteins, demethoxygeldanamycin and a number of oncoproteins. Most of the EGCG: (−)-epigallocatechin-3-gallate Hsp90 client proteins are involved in cell growth, EGFR: epidermal growth factor receptor 1 differentiation, and survival, and include kinases, eNOS: endothelial nitric oxide synthase nuclear hormone receptors, transcription factors, ERα: estrogen receptor α and other proteins associated with almost all the GDA: geldanamycin hallmarks of cancer. Consistent with these diverse Her2: human epidermal growth factor activities, genetic and biochemical studies have receptor 2 demonstrated the implication of Hsp90 in a range HIF-1α: hypoxia-inducible factor-1α of diseases, including cancer, making this chaper- HRI: heme-regulated eIF2α kinase one an interesting target for drug research. HSF1: heat shock factor-1 During the last few decades, plant secondary me- Hsp90: heat shock protein 90 tabolites have been studied as a major source for LPS: lipopolysaccharide lead compounds in drug discovery. Recently, sev- Met: mesenchymal-epithelial received Dec. 30, 2014 eral plant-derived small molecules have been dis- transition factor revised May 13, 2015 covered exhibiting inhibitory activity towards NF-κB: nuclear factor-kappaB accepted May 30, 2015 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Hsp90, such as epigallocatechin gallate, gedunin, NSCLC: non-small cell lung cancer Bibliography lentiginosine, celastrol, and deguelin. In this p-Akt: phosphorylated protein kinase B DOI http://dx.doi.org/ work, an overview of plant secondary metabolites PAH: polycyclic aromatic hydrocarbon 10.1055/s-0035-1546251 interfering with Hsp90 activities is provided. PI3K: phosphotidylinositol-3-kinase Published online July 30, 2015 Raf-1: proto-oncogene serine/threonine- Planta Med 2015; 81: 1223–1239 © Georg Thieme protein kinase Verlag KG Stuttgart · New York · SPR: surface plasmon resonance ISSN 0032‑0943 STAT3: signal transducer and activators of Correspondence transcription 3 Prof. Nunziatina De Tommasi TPH: triterpenes from Patrinia heterophylla Dipartimento di Farmacia VEGF: vascular endothelial growth factor Università di Salerno Via Giovanni Paolo II 132 84084 Fisciano (Salerno) Italy Phone: + 39089969754 Fax: + 390 89969602 [email protected] Dal Piaz F et al. Hsp90 Activity Modulation… Planta Med 2015; 81: 1223–1239 1224 Reviews Introduction inhibitors, such as radicicol, GDA, and 17-DMAG, are derived ! from fungi metabolism and possess the benzoquinone ansamycin Presently, the effective therapeutic interventions in cancer dis- (GA) or the resorcinol scaffold (radicicol). They are currently eases still remain elusive, thus the identification of new possible being evaluated in over 80 ongoing or completed clinical trials, molecular target(s) becomes crucial. In the last two decades, at- offering a promising approach for the treatment of different can- tention has been focused on the role of Hsp90, an evolutionary cer diseases [12,13]. conserved molecular chaperone involved in the regulation, fold- However, there is still a wide requirement for new Hsp90 inhib- ing, stabilization, activation, and assembly of more than 200 ”cli- itors, and the plant kingdom has been explored in order to find ent” proteins, including apoptosis-related protein kinases, tran- new promising compounds. This review provides a brief excur- scription factors, and signaling proteins, directly associated with sion of plant secondary metabolites interfering with Hsp90 activ- most of the cancer hallmarks [1,2]. Structurally, Hsp90 is a flexi- ities and highlights findings regarding their possible molecular ble homodimer including three distinct domains: an N-terminal mechanism of action. nucleotide-binding domain where the ATPase activity is mainly located, a middle client protein binding/ATP-hydrolysis regulat- ing domain, and a C-terminus domain responsible for dimeriza- Flavonoids tion of the protein [3]. Hsp90 exists in different isoforms: two in ! the cytoplasm, Hsp90α (the heat shock-induced form) and Flavones and flavonols Hsp90β (the constitutively active form), one localized at the en- Apigenin, chemically known as 4′,5,7,-trihydroxyflavone, is a doplasmic reticulum (94KDa glucose-regulated protein, Grp94), common flavone widespread in plants of the Asteraceae family one at the mitochondria (tumor necrosis factor receptor-associ- and in many fruits and vegetables. This flavonoid possesses vari- ated protein 1, TRAP1), and finally the cell surface-bound, cell-re- ous clinically relevant properties, such as antitumor and anti-in- leased and cell-secreted Hsp90 collectively known as “extracellu- flammatory activities [14]. Among its anticancer effects, it has lar Hsp90′′ (eHsp90). Several data reported in the literature sug- been reported to suppress metastasis, to inhibit cancer and cell gest the eukaryotic cytosol Hsp90α to be the major form involved proliferation, and to have antiangiogenic properties mediated by in cancer, also demonstrating that this isoform may have more the alteration of different pathways [15]. Anyway, it has to be diverse action than Hsp90β [4]. In the presence of stressed micro- considered that the metabolic activity of the gut microflora on environments, cancer cells undergo adaptive mutations that lead apigenin is often responsible for the modulation of its biological to an increment of Hsp90 activity. Therefore, in order to obtain a activity as a dietary compound, since itʼs catabolized into smaller simultaneous disruption of multiple signaling pathways impor- phenolic compounds [16,17]. In a study focused on the investiga- tant for the growth and viability of cancer cells, and to induce cel- tion of the antiangiogenic effect of apigenin, it was found that it lular apoptosis and/or necrosis, the inhibition of the Hsp90 pro- suppresses the expression of VEGF in endothelial cells via the tein folding machinery could represent a multifaceted approach degradation of HIF-1α protein mediated by interference with the toward the tumor treatment [5–8]. Hsp90 inhibitors are grouped Hsp90 chaperoning function [18]. Recently, the in vitro therapeu- into numerous classes based on individual modes of inhibition tic potential role of apigenin for the treatment of multiple myelo- which are as follows: i) obstructing the binding of ATP at the ATP- ma has emerged. Different biological techniques reveled that api- ase catalytic site, ii) interference in co-chaperone/Hsp90 interac- genin manifested antiproliferative activity in human multiple tions, iii) blocking the receptor interactions of client/Hsp90 alli- myeloma through CK2-mediated phosphorylation of Cdc37, dis- ances, and iv) intervention in the routes of post-translational rupting the Hsp90/Cdc37/client complex via the proteasome modification in Hsp90 [9,10]. Regardless of the mechanism, a pathway [19]. Moreover, its modulation of the chaperone Hsp90 hallmark of Hsp90 inhibition is the degradation of its client pro- induced the degradation of many kinase client proteins, includ- teins; the inhibition of this chaperone indeed leads Hsp90 client ing RIP1, Src, Raf-1, Cdk4, and Akt. proteins to adopt an aberrant conformation, which triggers their Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavone ubiquitination, followed by proteasome-dependent degradation. found in the plant kingdom (Passiflora caerulea L. and Passiflora Therefore, compounds able to downregulate the levels of Hsp90 incarnata L., Passifloraceae) [20–22] endowed with many biolog- client proteins are often considered promising Hsp90 inhibitor ical activities, such as anti-inflammatory, anticancer, and antiox- candidates. idant [23,24]. Although chrysin is a promising antitumor agent, Consistent with the notion that small molecules synthesized by little information is known about its molecular mechanism. It This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the plant kingdom can be considered evolutionary chosen “priv- was described that chrysin inhibits the expression of HIF-1α and ileged structures” since they have evolved in a natural selection VEGF in human prostate cancer DU145 cells [25]. In this study, it process to achieve optimal interactions with biological macro- was reported that chrysin inhibits the expression of HIF-1α by molecules, natural molecules have shown an extraordinary po- multiple pathways, including Hsp90 modulation. In particular, it tential as modulators of proteins