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    REFERENCIA 5 Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis_ a Review

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    REFERENCIA 5 Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis - A Review

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    Luis Fer JP

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    & nutrients (imbey ‘Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review (Changain Kim and Bonglee Kim *O ‘apartment of Pathog: Coleg of Konan Mesine,Graat Scho Kyung Ho Une 1 Hoong Dang Soul 18-7 Kors cae ar *Carmapondonc: bangle Ta 8229619217 Racine 25 Jn 28; Ascp 1 August 28 Publi 4 August 28 Abstract: Cancer isthe second biggest cause of death worldwide, Despite a number of studies being conducted, the efectve mechanism for treating cancer has not yet ech Fully understood, The tumoranicrocav iment sucha ypoks Low arent cou dist funciona endopas ticlum ER] to maintain cellar homestay ulimately lading othe accumulation of ule Proeinsin ER soll ER stress The ER stesshasa.close relation with cancer. ER stress ines Unfolded protein respense (UPR) to reestablish ER homeostasis as an adaptive pathway in cance, However persistent ER sess triggers the apoptotic pathway. Therefore, lacking the adaptive pathy of ER tres or fectatng the pop pathway could be an anticancer seatgy. Recent, atural procs an her derivatives have ben eporte to have anti-cancer effect ia ER stress ere, ve adres mechanisms of ER sess mediate apoptosis nd highlight stages fr concer therapy by ullzng ER sts, Futhermore we uml ant-ance oct ofthe natural pots vs ER stro in x major types cancers lolly (ang, bres, color, itr; prostate and ver "acer: This esew deepens the understanding of ER ses mechanoms in ajransers el 36 thesuppresive impact of natural panets against ances via ER srs, Keywords natural posts: iostve compounds cancer endoplasmic stress unfold protein response apoptosis 1 Intoduetion Cancer ca group of dincaes that undergo uneepulats cell roth an proliferation without stopping] Although overall survival term sincwesse slightly de tet detrtio, cancer-related ‘moray ithe sacond biggest cause of deuth worldwide [2], The Internationa Agency for Research on ‘Cancer (ARC) reported that 11 lon new cance eases at 82 milion deaths ook place workvide in 202, and 217 milion cancer incidences and 13 milion deaths were predicted in 2030 Among sven iypes of cancers, ing bres, colons gastric, pons and liver cancer were selected asthe major cancers in human being. These ances represent 5% ofthe global cancer incidence aren in 2012 Themechaniuns of cancer accummce and prgreion aro filly undentood yet. The proiferston| ‘of cancer originated from it ability to ac programmes cel death, eae apoptons [i-That ‘shy induction of poptois in cancer as bee denied a gt for testnet of cancer [Up ro, nducton of apoptosis x conducts by two main apoptotic pathways intrinsic an extrinsic pathway [7] ntrinepathway is iochondremedited apoptosis which is madied by cytochrome (Crleae and activation of anpases stimuli tector caspases, capase Earns pte sath receptor (DR) mediated spptons which acta the FAS eat ath domain FADD) ae fons the death-inducing signaling comples (DISC), which processes dowtream caspases ching ‘easpase8-7-, and 3 [5]. However, studies have identified thatthe accumulation of unfold ‘proteins in endoplasmic ticuli (ER) st cellule ste response i involved in apoptosis Fnccatnginflunce of ER on cell fate a thi suber compartment [0 ters of ER Stes: A Doble Edged Sand Cal Suc or Death? Rsan organelle inthe eukaryotic cell tat responsible for protein yates an calcium (Ca) ‘signaling lao provides stable enronmen flip, teri on holst binges Moreover, the main oes of ER incu maintenance ofomeostois in inraceular Ca storage and the folding of protein destined tobe secrete on te plasma membrane [2]. Poin are tansocated Info ER himen ond undergo post translational medication for fidelly of synthe, folding and ‘corecting function. Alter panting ER, proteinn ae propel foled by a network of ehaperooes [3 However exes ella envionment challenges nich vcs nye species (HOS), PypONS, and nutrens deprivation could induce disturbance in cellar rox regulation of ER, lang fan imbulance in homeostasis. Thus, the physiological fancion of ER and the ER protein olding ‘vironment ate inp, ultimately resulting in the accumuaton of unfolded pein in the hamen ‘oF the Ektnarsely, ER sts [Il] Pir ste have demonstrate that both ER stress ad the sctivation of unfolded pte exporue(UIPR) ae nected with pathologe proces, lang reurodegenerative disscescondovsscla disses and cance [Because ofthe api expansion ‘ef malignant neoplase, cancer cells are exposed ol nutes por vascularization, and hypoxa So thot ER stesseated preinsinludngglacose-egulte protein 75 (GRP7S binding poten (Gi, gocose regulated protein 94 (GRP 9, ER asst degradation (ERADY, protein disulphide isomerase (PDD activating tarsription factor 6 (ATFO) inositol requiring protein (REN, box ‘ining protein 1 (XBP!), protein kinase RNA ike ER kinase PERK) and eukaryotic ination factor 2 eliza are overeypressed in many typos of ance ell [15-17]. In response to ER sess. on ely phase the cel inate UPR to mate proper potsin folding al degradation of unfolded protein ‘san adaptive pathway for survival. Under Estes, GIEP7S/ Bi eich originally Bin the Tuminal domain of three ER transact sensors: IREI, PERK, and AT, dissoites rom hese hse ER transducer sensors. The thee ERJovaliz tancmembvane signal ansduces of UPR’ ATF, TRE! and PERK detect accumulation of unfolded prosins and inate orestore and antin the ER homeostasis [5 Moreover ERAD Ss increased stent unflded pin accumltion ean protein oding capacity in ER and ER capers (GRP 94, GRIZS/ Bi ainsi) which are elevate {ostablize protein folding. However {FER stress prolonged to the extent that UPR is unable to ‘ope with unfolded proters, UPR is promoted tobe turned io apoptotic machineries by transducing, ‘poptoticdownstieam pathways through ATES, PERK. and IRE sigraling pays [1] 2 Ant-Cance Stztegy Based on Adaptive Pathway of EK Stress in Cancer Growth Cancer calls evolve UPR to mitigate the ER stress conltion as a survival strategy for progression 2. Also, UPR in cance reported to have significant oles in having estance to ‘chemotherapy or radiation [721] Therefore, one therapeutic raonale regarding suppression of ‘oncers to facta the ceutulation of nfl protein by inhibiting component of UPRinvolved insurvval esponse ultimately leading to apoptsis 221 Figur I). AARAARARARAARARARARRARAARAAAAAAAAARARAA UUUUUUUUULUUELLUUUUUUuE Ue EEE i uae Figure 1 Adaptive pathaays of edplamic mecl ER) wet ER st iced by 2 28 IGRI7 bing roti (BP) snes ome ineraton with he hee ER se sera InouioLeguirng protein 1 ARE!) pin hnaee RNA ie ER Kine PERK} and attng transcript co 6 (ATF, wich bom aad, IRE mi spicing of eon binding prin ABP), which sensi orth upulaton of ER soca ation (ERAD). PERK phosphors Fann ativan tasrpin factor 4 (ATE) whichis inven ‘ering ER nests ATF clave by apecic ol det poke ree expe 2.1, AnisCaner Strats Tngetng ATFSa GRP Signaling A frst modulator of ER stress signaling i ATF6a-GRP7S/BP: During ER stress conditions, sven of GRE7S/ Ea rom ATF alos hs protein translocate Gl appara here “leaved by specific Golgi siden proteases [25 Ths process forms ATFsa, which produces ative leansription factors that are involved in upegulating ER chapezones and ERAD [2 In ado, ATFs contributes to tansrpion factor XBP, eich targets the ERAD [25] (gue 1). Further, the expres of GRP75/BiP is elevated partcaly in liver, colon, prostate, bret, lang and ‘gastric cance [625], The elevate expression of GRPZS/BiP is reported o correlate with cancer proliferation, chemotherapy resistance andl poor patient survival rate by modulating accumulation ‘unfolded protein folding [>In aditon, GRP78/TMP induces angiogenesis by activating the potent prenangiogenic factor, vascular endotli growth factor A (VEGF-A) [2] Recenly, tdi have confirmed that krockowen of GRD7S/B by siRNA ean inhibit carcinogenesis and sensitize ‘ance cls to chematherapetic agents well as ER sts (395), The GRP7S/ BP inhibitor exert ‘ytotxcity against leukemia [35] ana glioma cancer cells [i]. These observations suggest that “ring ER sts, ition of the ATF-GRD7S/BP sigalg pathway could bea state) for cancer therapy [57] For ample dhe knockout of GRP7S resulta in deresed proieration rts loa ‘lle and suppressed TEN nl prate tumorigenesis and AKT onogenicpatay [3 2.2, AnsCancer Strategy Targeting IRELa-XBPI Signaling A second modulator of ER stes signaling is IREIe-XBP1. Two isoforms of IRE, IRE and IRELB, have been identified. IREIa is expend ial cll type, but the expression of TREY ix postaly resco the intestinal eptheium [7], In cll underpin ER te, activation ‘FIRE stimulates an endovibonuclease that spices XBP1 mRNA to produce mature XBPI. XBPL ‘encodes an active leucine ipper (62) taneriptions factor that generates transcription of genes Involved in ERAD components as well as genes involve! in rox homeostasis an ondative tess response (Figure 1) [412], The tvlvernent ofthe IRELa-XBPI signaling in cancer progression hasbeen the subject of many stds. Upregulstet XBPI expression is screed in varios man ‘ances including best cancer ae hepato crcnoma [1] NBPeficent ance cells shes hypersensitivity to ER stesso hyposa condition |. Moreover, expression af the dominant negative foumof Ela or inition of XBP1 by siRNA induces reduction nanogenests during tumorigenesis asad i cancer groveth ia xenogeafts model [05,005 Adaionaly, inubition of IRELeXBPL ‘enhances apoptnsisy dven-ulaing real genes involved in UPR and generates active oygen “species (ROS) in XBPI icin el [5]. Those results provide evidences that eeactvtion of the TREL»XBPI [SF cou bea tanget of anticancer therapy. For instance IREla inhibitor rendered reistant human gobastoma ell susceptible to oxidative stress [7] Inubion of IRE decried ‘endonuclease actiiyinresing \totoue actity against human mliple myeloma in vito and ivi [i8) 2, AnsCancer Steg Taglng PERKeIF2e ATF Siting Athi modulator of FR tes sgnaling the PERK signaling pothwvay: Under ER sts ‘conditions activation of PERK phosphorylates a Se3 [Phosphorylated 2a shuts dw [rein nf into the ER amen and ttersates mRNA translation, edacng poten synthe [51 ‘The activation of PERK-elF2a increases the translation of number of mRNAs encoding activating, leanscripion factor 4 (ATES) [2]. AT promotes cllsueical by contol amino aed biosynthesis and transport function, as well as aniowdant stress responses [5] PERKelF2«-ATE signaling athray ts esponsble for cancer growth and esistnceauiat crave treatment. The UPR sigoaling pathway through the PERK-elF23- ATES signaling pate als increases tolerance in cancer cls hypoxic tess [17 naddition the PERK-eIF23-ATF signaling pathway incancecllsmelates the ‘upregulation of VEGF-A uanscrpion 17. Rocnly i has ben epevted that PERK deficient cel are hypersensitive to ER tens [i] ad nition of PERK suppress cancer cls which are rent racaton in vivo 5}. These resi gart hat suppress of PERK el F25- AT signaling patos ‘ould bes target of ance therapy Fr example, transformed mouse embryonic roblat rom the PERK deficient animals and HT29 colorectal cinoma ells sith dominant negative PERK had ower survival tes under hypone conditions than wildtype contol els (5), And thes calls displayed ‘tral cancer-formation and increased the level of apoptotic activity in hypane ares, compared teil celle [7] Im aii, PERK cfcent concer ells ext declined sity 4 nde nglogeneis in responce to hypo ste [7] [8 AmiCancer Strategy Based on Apoptotic Pathway of ER Stress in Cancer Growth GER sts perso is aggravate cancer cll fil fo r-estblsh ER homeostasis via UPR ERR “tres swtches fm po-sursval fo pro-apoptotic comin [5], Therefore, faitation of Esra o Iniate the apoptosis patoay could bea therapeutic strategy fr ant-ance activity 14.5) (gue 2) 31 Anti Canser Stoo Taging CHOP Mit Apptane During the prolonged Estes condition, PERK is activate and phosphorylates elF2x [ Phoxphoryitnd ef2a ssequenty activates ATI hich tages the expression of apoptotic eestor ‘CHOP (C/EBP-homelogous protein known as GADDIS3, GENE name Dat) ol. Furthermore, ATFs als activate a tascrpinally laces CHOP [2]. CHOP meted ell ath ent the Induction a a variety of genes tha may potentate apoptosis inlading GADDSH and ERO [5] ‘GADDSs, a tanscriptional ange of CHOP, encodes a subunit of pelea phosphatase that promotes -dephosphoryation of P24 tat eis esumption of protein synthesis intr incesing helo of ‘proteins [ol Accordingly, ER stress activates the UPR to nts donnsteam of apoptotic pathy Inadaition, CHOP is thought to elevate the expression of Eola which catalyzes the re-osidation af PDI, leading to hyperoniizing conditions inthe EK [5], The CHOPndace experanion of ERO ‘activates the ER Co" release channel, inositol 14.5rphosphate (PS) receptor PSR [8]. Then, ‘ytoplsmnic Cae release fom the ER triggers the activation of caleum/calmodulinlependeat protein kinase I (CaM, sltimatey reign the indctom of apoptoss pathy [i Furthermore, CHOP mediate apoptosis involved in extrinsic pathway trough upteguating DRS alongwith capase activation Which cleaves Bd (Bi) and translocates it to mitochonea [7 In addition, CHOP is shown to decrease the expression of ant-apoptoic B12 and Bell proteins, ‘whe increasing the expresion af pr-apoptos: proteins ecg Bk, Ba, IM (Bel 2k poten 1), PUMA (ps uprguloted modulstr of apoptosis) and NOXA (PMAIDI) (Figure 2) [70 Thewe -tuios imply that up-egltion of CHOP expression could he an trative tage or ance therapy: Forexample, CHOP leficency elevates cancer development na Kras°™ nde mse smodel of lang carcinoma [i]. Aad hepaoeyte-specie CHOP deletion cases encore i ‘mouse ode of hepatocellular carencena 72 IAA if uu gute 2 Appt pata of ER srs Ifthe adap UPR pathy alle to ress hoses {TNE reepor associated ate TRAP) al apopons sigalg Kinase 1 (ASK, TRAF2 stimulates the activation of easpse2 and ASK ls the phosphoyation ofc an-N tema {nme NK) ota he prospepoi prin lhe protein 1 (HM, Bak, Bo anni ‘heap poten Bes Imiphoma2 (B 2), Beat prin (Bo). Acton of prsapopotic protein BM, Buk, Bs, 3 upregulates modulator of apoptss (PUMA), NOXA as well. Inner mite mae, wesling mn Mischncil ROS Appts ptt tot (Apt FAS ues eth aria FADD) 32. AntiCanser Stoo Tasting IREL Mit Appts Under conic ER stress, IREIa 8 induce to activate the mitogenactvted protein (MAP) kinase (MARK) 73}. The IRE binds with the adaptor protein, TNF receptor aseiate factor? (CTRAP2),IREIo-TRAF? comple triggers the activation of capase12, eich s homologous to human ‘aspase-t [7s] Cospose-12tansiocntes fom the ER to the cytosol, shen it intistescleaage of procaspase in tum activating de efector caspase, caspase 75,76. TRELa/TRAF2 activates ASKI (opoptnisgna-uating kinase I), which sumequently promotes activation and phowporlation ‘of chur-N terminal kinase QNK) [7]. The Phosphoryation of JNK activates IM, Bak, Bax and inhibits the B-2 an Bex Figure 2) 757). These data implicate thatthe teiggerng REV -mediatet apoptosis could be astategy for an-cancer therapy Fr instance ER stress mediated apoptosis Was ‘reduced in IREI-deicent mouse embryonic ibroblasts [i]. And deactivation of ER ster mediated poptonis in INK inhibitor treated wikt-sype mouse embeycnie Hbrablss as conten [| 33. Anti Cancer Sete Tigting Gocraton of ROS Maite Apoptosis ‘When ER stress persists it hyperoxiizes the ER lumen, reslng in HO> leakage int the uptake in mitochondria depelaries the nee mitochondrial membrane leading mitochon ROS _neeration [] Then, BI. protsins, ak and Ba, oligomerize and inert themselves nt the ‘outer mitochondrial membrane 1 increase permeabilization, resulting in the release of eytecoe [671 When cytochrome cs elesed with the formation of APAFI apoptosis protense-activaing, factor 1 and procaspase9 [caspase [°) apoptsisinducing factor (ATF and endonuclease G (Endo) are activated [ln general cancer celle istrnniclly have more ROS compared to normal ‘lle Theor, elevated generation of ROS render cancer cells more uncepble 0 ER stews which contributes to ER stress meted apoptosis [1]. Thus, the generation of ROS could bea target of anticancer therapy: In vito, ROS dependent ER sues activation and mitochonda-elatedapoptoie pathway were identified in MDA-MB-23 and MCF call lines wih rstment of beer [2 Panlanin-triggred ROS-dependent ER sts and its apoptotic activation via ER ss were inhibited byNAC tetment [5 ‘The standardized treatments of cancer consist of surgery chemotherapy radiation therapy and imamunotherapy. These are utlized in accordance with the chiraciers and sages ofthe cancers Although the min purpose of anvcancer tentnents isto Kl the cancer cells without dsmaging norma cel cancer tweatments possess limited effiacy and exert ther actions on both malignant and nodal cls, sling in adVerse efecto patents, cluding anemia oso petite deliium land peripheral neuropathy. Thus, dhe development of elfctive treatment which has anircancee cist with los adtverse eft i sill coded [9.5]. From the history of drug discovery natural ‘recuct-lrived compounds could be promising treatment due to thee characteristic induce Spoptosis more commonly in cancers sompans to normal ell 7. nfs, several conventional ‘chemotherapeutic agent including Taso, epedtlones,vnca alkaloids originate rom the source of ratral prac [25 Caren as ER treme respec proverta have oth an adaptive pathy and apoptotic patheay, modlaton of FRstrewe co bean anticancer strategy: Therefore, esotchers have focused on th inerplay between natural products and an-caner fect wa ERstress malignant ll in vito and in vo [101], Hence, a this weve artic, ant-eneezous mechanisms of natural ‘products onthe most common cance pes ia modulation of ERs ae discussed Lng, beast, ‘loreal, gst, prolate ver cancer, hich represent 55% ofthe global incidence burden i a2 Pa Researches raring the ER stss-medited apoptotic of natural product on ances were Callum Re Peel, Ns Males M: Chiou, Js Fauve Fs Payen Le ior. nn, TSK testi he preapptn erkchop pathway allows mignon pron po co, Ma Cai 254, 19-108 [mt faked) 72 Nabngna Hs Uma, A: Tnigach K: Font Baza, Do Ot, Ms Zhong, Z Vols MA Soh Es Miao Estes cooperates wth hyprnteton wo trigee TNF pent sprtanes ec eslopnent. Cc C1204, 26, 31 Cs Pass) 7. Maula, eMac, Toes, Ke The ASKI-MAP kinase cnadein a teepone J ch 00,136 26-25 [o [Mes 24 Facer; Koi Usha; Toh E Hanan capone 12 ha acquit mutton ko Bp Res. Commun. 22,293, 72-72 (Creates) [Dhanssarn DIN Rely EP INKsigalingi appt Once 208,27, 425 (ist [a ‘one, Tl, Ke Oo, KY D; Gar Fe Kayan, Ts Taya, M.Acttion of apace 2, sm cadet ecu (Frese asses tamor ern ctr cepa fcr depen mechan neste ts | Ba Cha 2M, 275 SBM Ket PNT 7th; Matuza,A Tele Ke: Saag, Kak Kslnoue KH Soke, AI, hte epee Gras D0, 16-185 [Cosel [Me 2, Hans C:A:Jhnon, EM BEcnlyBel2 fly membesarecowsiy regu byte INK pay nage Bos once ppt | Ba Che 201, 276 377347, Pu} YU. Minemot, Yen JL. Tang, Bah EN Nag. Lin A INK suppress poptssit Phonporynon ofthe appt - frly pti Mal Cl 206 1, 58-3 fs] ‘rano F; Wang X: Bert As Zhang, Chung Ps Haring HP: Ren, Coupling of tes inthe [Eo nchationot INK protein kinases by tansmambeane pn Kise RE, Ske 20297, co 6 [ros abs SL L.JENE Moe Boron Hino, DLA. The fie protein espns elt GRIPS/ Bi ‘ee for enoplasmielen egy and stsendc autophagy naman cells Cl Dh Dif 2m, 5 a7 ers Pues (2 ang Ys Cus SoH Shang XN LS; Za JN Zhao, As Zh, YF: An, GH Zhang Ma, 8 Teptotide indces sere cel pps in mice vis ROS/TNK dependent atin of the mocha patsy and into of Nelle antonan apr Ate Part Si 20839, 310-327 [eros bos 9. Zhang Y Chen F Reactive cage speces ROS robles ween nce ten (NF) a ‘Ju tial ae JNK} Caer 2906, 182-105 [sal Paes |S Kowal AJ Nate, ES: Castth, Veen AF Ca timated macho rect ‘npg pcs neston ae pernebity ranstion ei by acne or MS Ath Bach: ye 19838 7-8. [cst Pe 45, Tn. Druin N; WC: De Ver, Fe [Ss Gret PA Uigutsapuine promotes 12a INK acatonduring endoplasmic macaw nc pops [Bl Che 208, 2 16016-1 [cron aa Duchn ALR Contato f tochonds animal pysnogy Frm amo ensr ta cat signaling ore death Pgs 199, 6,17. (croste Pel wana BouchierHayes,L; Chik, JE: Bonn. Silvan, BA: Geen, DR: Newer DD. prmebioton bt dety p iet Mol Cl 208,17, 52-58 [msl [se | Hho, Z: Dusan, Chang C-C: EAs Fag, Mt; Wakeham, A; Oka H Calas, Tan: {ure A Spee abltin a the apoptotic anions of ecm C reveal deri ment foreyachane Cand Aplin apptns C2208, 121 5591. [ral ss | LLP Nifowan, D; Bodandp (Srna SM Amd. Mi Alt ES: Wang, Cytochrome cand ‘ent amt Ae camp appt pa mee Ca 1 LLL stun X; Wang X. Enon Gan po dase wh ened rindi, Ne ot 2.9.9, cms Pas] Ba 91, Sebroiove Marjo. Cegado C: Fy Ds Zhang Fe: Kounis CCavent D:D PERK promots

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