ReviewCancer

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaal2323
DOI: 10.1126/scisignal.aal2323

Figures

  • Fig. 1 The three arms of the UPR.

    All three ER stress sensors (PERK, IRE1, and ATF6) initially activate signaling events that increase protein-folding capacity and reduce protein load on the ER. These transcriptional and translational outputs (listed in the nucleus under the respective ER stress sensor–mediated pathway) tend to reestablish protein-folding homeostasis in the ER and promote cell survival. JNK, c-Jun N-terminal kinase.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 The transcription factor network associated with the arms of the UPR.

    All three ER stress sensors (PERK, IRE1, and ATF6) activate downstream signaling events that directly affect cancer biology. The pathways underlined in black have been described in human GBM. Arrows, positive regulation; dot-end, negative regulation; AP1, activator protein 1; ASK1, apoptosis signal–regulating kinase 1; BIM, Bcl-2 interacting mediator of cell death; casp11, caspase 11; CREB, cyclic adenosine monophosphate responsive element binding protein; CXCL, C-X-C motif chemokine ligand; DCN, decorin; FGF6, fibroblast growth factor 6; GSTA, glutathione S-transferase alpha; mTOR, mechanistic target of rapamycin; NQO1, NAD(P)H quinone dehydrogenase 1; SKIP3, SKP1-interacting partner 3.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 3 Epigenetic regulation in ER stress signaling.

    Histone deacetylases (HDACs) and HAT-mediated regulation of ER stress signaling through chromatin remodeling in the nucleus and through posttranslational modification of select proteins in the cytosol. The pathways in black have been described in human brain tumors. CBX7, chromobox 7; EGR1, early growth response 1; SIRT1, sirtuin 1.

    CREDIT: A. KITTERMAN/SSCIENCE SIGNALING
  • Fig. 4 UPR in the reciprocal communication between tumor and stromal cells.

    In tumor cells, activation of the UPR and its downstream effectors [ATF4, nuclear factor (erythroid-derived 2)–like 2 (NRF2), XBP1s, and ATF6] triggers the transcriptional program contributing to cancer hallmarks, including invasion, metastasis, deregulation of cellular energetics, and sustained proliferation. In addition, the UPR modulates the tumor microenvironment by inducing the production of proinflammatory and proangiogenic cytokines and chemokines. Once released, the latter shape tumor stromal cells to support cancer progression and resistance to treatment. Upon binding to VEGF receptor 1 (VEGFR1) on endothelial cells, tumor-secreted VEGFA induces a UPR that supports endothelial cell survival, proliferation, and migration in an AKT-dependent manner. In turn, new blood vessels are formed, providing the extensively growing tumor with oxygen and nutrient supplies. Other UPR-regulated secreted factors trigger the UPR in tumor-infiltrating immune cells. As a consequence, those cells produce proinflammatory cytokines and lose their ability to cross-present antigens, thus enabling tumor escape from immune surveillance.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING

Tables

  • Table 1 Drugs targeting the UPR.

    Names, structures, and target of molecules identified to target directly the ATF6 (green), IRE1 (pink), or PERK (yellow) pathways. All the molecules indicated are inhibitors except for compounds 147 and 263 that activate ATF6.

    PathwayNameStructureTargetReference
    ATF616F16Embedded ImagePDI(58)
    CeapinsEmbedded ImageATF6(126, 127)
    Compound 147Embedded ImageActivators of
    ATF6
    (128)
    Compound 263Embedded Image
    IRE14μ8cEmbedded ImageIRE1 RNase(129)
    MKC analogsEmbedded ImageIRE1 RNase(130133)
    3-Ethoxy-5,6-
    dibromosalicylaldehyde
    Embedded ImageIRE1 RNase(130)
    KIRA6Embedded ImageIRE1 kinase(134)
    STF-083010Embedded ImageIRE1 RNase(135)
    Compound 3Embedded ImageIRE1 kinase(136)
    PERKGSK2656157Embedded ImagePERK(44)
    ISRIBEmbedded ImageeIF2β(137)
    SalubrinalEmbedded ImageGADD34 (PP1c)(138)
    GuanabenzEmbedded ImageGADD34 (PP1c)(139)
    Sephin 1/IFB-088Embedded ImageGADD34 (PP1c)(140)
  • Table 2 UPR modulating drugs in GBM.

    Molecules used in GBM models and reported to act through the modulation of ER proteostasis. HSP72, heat shock protein 72; Hsc70, heat shock cognate 70.

    ModelDrug nameLink to ER stressCellular impactClinical
    trial
    (yes/no)
    Reference
    In vivoHuman
    cell lines
    2,5-Dimethyl-celecoxibGRP78 and CHOP inductionApoptosis inductionNo(151)
    Δ9-TetrahydrocannabinolATF4, CHOP, and TRB3 induction and
    eIF2α phosphorylation
    Apoptosis induction, reduced
    tumor growth, and autophagy
    Yes(152, 153)
    Asiatic acid (2,3,23-trihydroxy-
    12-ursen-28-oic acid, C30H48O5)
    GRP78 and calpain induction,
    calnexin and IRE1α down-regulation
    Cell death inductionNo(154)
    Epigallocatechin 3-gallate + TMZGRP78 down-regulationIncreased mice survival and
    increased glioma cell
    sensitivity to TZM
    No(22, 155)
    NEO212 (TMZ conjugated to
    perillyl alcohol)
    CHOP inductionCell death inductionNo(156)
    Perillyl alcoholGRP78, ATF3, and CHOP inductionCytotoxicity and decreased
    invasion
    Yes(157, 158)
    PiperlongumineCHOP, eIF2a, ATF4, GADD34, and
    GRP78 induction
    ROS-induced cell deathNo(159)
    In vitroPrimariesRDC11GRP78 and CHOP
    induction, and
    XBP1 splicing
    DNA damage and apoptosis
    induction, and cell growth
    inhibition
    No(66)
    TMZ + chloroquineCHOP inductionAutophagy inhibition and
    apoptosis induction
    No(160)
    2-Amino-N-{4-[5-(2-phenanthrenyl)-3-
    (trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}
    acetamide (OSU-03012)
    Involvement of GRP78 and
    PERK pathways
    Cell death inductionNo(161)
    Celecoxib + sildenafileIF2α phosphorylation and
    activation of ATF4/CHOP pathway
    Autophagy and cell death
    induction
    No(162)
    Terpyridineplatinum(II) complexesGRP78 inductionPerturbation of redox metabolism
    and cell cycle arrest
    No(163)
    Human cell
    lines
    TMZ + SKI-II (4-((4-(4-chlorophenyl)-
    2-thiazolyl)amino)phenol)
    GRP78 and CHOP inductionROS-induced cell deathNo(164)
    Withaferin AGRP78, IRE1, and CHOP inductionROS production and apoptosis
    induction
    No(165)
    2-Deoxy-d-glucoseER stress response gene signatureIL-8 inductionNo(166)
    2-Deoxy-d-glucose + cisplatinGRP78 inductionAutophagy inhibitionNo(167)
    2-Hydroxyoleic acidIRE1α, CHOP, and ATF4 induction,
    XBP1 splicing, and eIF2α
    phosphorylation
    Cell cycle arrest and autophagy
    induction
    No(168)
    5-Androstene 3β,17α diol (17α-AED)GRP78 and CHOP induction, and
    activation of PERK/eIF2α signaling
    Autophagy inductionNo(169)
    Amiodarone + TRAILCHOP inductionApoptosis inductionNo(170)
    Antp-TPR hybrid peptideGRP78 and CHOP inductionCell death and cytotoxicity
    induction
    No(171)
    BerberineGRP78, CHOP, and PERK induction,
    and eIF2α phosphorylation
    Apoptosis induction and ROS
    generation
    No(172, 173)
    BufalinGRP78 and CHOP induction, and PERK and
    eIF2α phosphorylation
    Apoptosis and autophagy
    induction
    No(174)
    Candidaspongiolide (CAN)Activation of PERK/eIF2α signalingApoptosis induction and protein
    synthesis inhibition in normal cells
    No(175)
    CelastolHSP72 and HSP90 inductionAutophagy induction and
    accumulation of protein aggregates
    No(176)
    Celecoxib + γ-irradiationCHOP inductionCell cycle arrest and autophagy
    induction under hypoxia
    Yes(177)
    Celecoxib/2,5-dimethyl-celecoxib + bortezomibGRP78 and CHOP inductionApoptosis inductionNo(65)
    Copper (Cu)GRP78 induction and aggregationROS generationNo(178)
    Cyano enone of methyl boswellatesActivation of IRE1α and PERKApoptosis inductionNo(179)
    Fatsioside APERK and eIF2α phosphorylation,
    and CHOP induction
    Apoptosis inductionNo(180)
    FluoxetineActivation of PERK/eIF2α/ATF4 and
    ATF6/CHOP signaling
    Apoptosis inductionNo(181)
    GlucosamineGRP78, IRE1α, and eIF2α inductionAutophagic cell death inductionNo(182)
    Nelfinavir/atazanavirInduction of GRP78, CHOP, and
    PERK/eIF2α/ATF4 activation
    Cell death induction and
    accumulation of protein aggregates
    (misfolding)
    Yes(22, 67)
    Minocycline (7-dimethylamino-6-
    desoxytetracycline; Mino)
    PERK/eIF2α/CHOP and IRE1
    activation, XBP1 splicing, and GRP78
    induction
    Apoptosis and autophagy
    induction
    No(184)
    Phenethyl isothiocyanateGRP78, CHOP, XBP1, IRE1α,
    and calpain 1 and 2 induction
    Apoptosis induction, decreased
    migration and invasion, and cell
    cycle arrest
    No(185187)
    Polyether ionophore antibiotics
    (monensin, salinomycin, nigericin, narasin,
    and lasalocid A)
    CHOP and ATF4 induction, and
    eIF2a phosphorylation
    TRAIL-mediated apoptosisNo(188)
    Prenyl-phloroglucinol derivative
    [2,4-bis(4-fluorophenylacetyl)phloroglucinol]
    GRP78, GRP94, IRE1, and CHOP
    induction, and eIF2α
    phosphorylation
    ROS generation and apoptosis
    induction
    No(189)
    Quinine, quinacrine, mefloquine,
    and hydroxychloroquine
    CHOP inductionApoptosis inductionNo(190)
    S1 (BH3 mimetics)GRP78 and CHOP induction, and
    IRE1 activation
    Apoptosis and autophagy
    induction
    No(191)
    Schweinfurthin analogseIF2α phosphorylation and GRP78
    induction
    Inhibition of cancer growth and
    apoptosis induction
    No(192)
    Sulindac sulfideGRP78 inductionCell death inductionNo(193)
    TMZCHOP inductionNo(22)
    Unsaturated fatty acids + irradiationGRP78 inductionIncreased radiosensitivity and cell
    death induction
    No(194)
    Zoledronic acidIRE1 inductionApoptosis inductionNo(195)
    Other cell
    lines
    Ursolic acidActivation of PERK/eIF2α/CHOP and
    IRE1/JNK pathway
    Apoptosis and autophagy
    induction
    No(196)
    ValproateGRP78, GRP94, calreticulin, and
    CHOP induction
    Inhibition of proliferationNo(197, 198)
    WogoninGRP78 induction and eIF2α
    phosphorylation
    ROS production and apoptosis
    induction
    No(199)
    YessotoxineIF2α and PERK phosphorylation,
    and XBP1 splicing
    Cell cycle arrest and protein
    synthesis inhibition
    No(200)
    CarbamazepineGRP78 inductionUnknownNo(201)
    Cyclosporine AIRE1α and PERK phosphorylation,
    and GRP78 and CHOP induction
    Apoptosis and autophagy
    induction
    No(202, 203)
    DesipramineActivation of PERK/eIF2α and ATF6
    signaling, and CHOP induction
    Autophagy and apoptosis
    induction
    No(204, 205)
    EthanolHsc70, GRP78, and GRP94 inductionUnknownNo(206, 207)
    Lead (Pb acetate)Modulates GRP78 mRNAUnknownNo(208, 209)
    Mercury (HgCl2)Increased GRP78 protein expressionOxidative stress modulationNo(209)
    Oleyl glucosaminide derivativeGRP78, CHOP, p8, and RAPM4
    induction
    Cell death inductionNo(210)
    Sesquiterpene coumarin DAW22GRP78 and CHOP induction, and
    PERK, ATF6, and IRE1 activation
    Apoptosis inductionNo(211)

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