The Unfolded Protein Response in Breast Cancer
Abstract
:1. Introduction
2. The Unfolded Protein Reponses
3. Aberrant UPR Signaling in Breast Cancer
3.1. IRE1/XBP1s
3.2. PERK
3.3. ATF6
3.4. GRP78
4. UPR Signalling Promotes Therapy Resistance in Breast Cancer
4.1. IRE1/XBP1
4.2. PERK
4.3. ATF6
4.4. GRP78
5. UPR-Targeting Drugs: Stand-Alone and Combination Therapies
6. Future Perspectives and Challenges
7. Conclusions
Funding
Conflicts of Interest
References
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Inositol-requiring enzyme (IRE1) | |
Luminal domain | p.P75Q, p.A371A, p.H386fs*8 |
Transmembrane domain | p.L454L |
Cytoplasmic domain | p.Q495_L496insQ |
Kinase domain | p.G703D, p.L714L, p.V767A, p.R806C, p.A823V, p.F937F |
X-box binding protein 1 (XBP1) | |
bZIP/nuclear localization signal | p.R81fs*16, p.R90P |
bZIP/leucine zipper | p.E108delE, p.E121D |
Translational pausing of own mRNA | p.L236fs*16, p.L238fs*13 |
Other regions | p.P8P, p.P37A, p.Q43E, p.E97delE, p.S187fs*6, p.S190fs*1, p.P213fs*45, p.L232fs*22 |
PKR-like ER Kinase (PERK) | |
Luminal domain | p.R114I, p.S385R |
Cytoplasmic domain | p.T537T, p.R588P, p.D1081fs*31, p.L1088L, p.S1098L |
Cytoplasmic/kinase domain | p.S686F, p.C788C, p.R797T, p.R1027G, p.E1050D |
Activating transcription factor 6 (ATF6) | |
Cytoplasmic/transcription activation | p.E25Q |
Cytoplasmic domain | p.Q237 * |
Cytoplasmic/basic motif | p.R309K, p.K327N, |
Cytoplasmic/bZIP | p.E365Q |
Luminal domain | p.A450fs*7, p.C467fs*1, p.L477F, p.R484Q, p.S592S, p.R624S, p.S631L |
Glucose-regulated protein 78 kDa (GRP78) | |
Signal peptide | p.L13L |
Nucleotide-binding domain | p.I132T, p.K138N, p.T166T, p.E243K |
ATP-binding | p.A295fs*28 |
Other regions | p.E308Q, p.E514Q, p.E603E |
Inositol-Requiring Enzyme 1 (IRE1) | |
RNase domain inhibition | Toyocamycin [93], MKC3946 [94], 4μ8c [95], 3-Methoxy-6-bromosalicyl-aldehyde [96], STF083010 [97], Doxorubicin [81], MKC8866 [24,30], B-H09 [98], 2-hydroxy-1-naphthaldehyde [99] |
Q-site | Quercetin [100] |
Kinase domain inhibition | APY29 [26], Sunitinib [101], Compound 3 [102], KIRA6 [26], KIRA8 [103], UPRM8 [104], GSK2850163 [105], FIRE [106] |
Not determined | Resveratrol [107], 3,6-DMAD [108] |
PKR-like ER Kinase (PERK) | |
Kinase inhibition | GSK2606414 [109], GSK2656157 [110], AMG PERK 44 [84] |
Kinase activation | Compounds A, B, C [111], DHBDC [112] |
Inhibit downstream effect of EIF2A | ISRIB [113] |
Promotes maintenance of EIF2A phosphorylation | Salubrinal [114], Guanlabenz [115] |
Activating transcription factor 6 (ATF6) | |
Inhibit nuclear translocation | CEAPIN Class 1 [87] |
Inhibit transcriptional activity | CEAPIN Class 2 [87], |
PDI inhibitor | PACMA 31 [116], RB11-ca [117], P1 [118], 16F16 [119] |
Prevent AFT6 cleavage (Serine protease inhibitor) | AEBSF [120] |
Not determined | Melatonin [121], Compounds 147, 263 [122] |
Glucose-regulated protein 78 kDa (GRP78) | |
Reduce GRP78 levels | OSU-03012 (AR-12) [123], Deoxyverrucosidin [124] Plumbagin [92], HA15 [88], DHA [125], |
Inhibit GRP78 activity | PAT-SM6 [90] |
Block GRP78 transcriptional induction | Arctigenin [126] |
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McGrath, E.P.; Logue, S.E.; Mnich, K.; Deegan, S.; Jäger, R.; Gorman, A.M.; Samali, A. The Unfolded Protein Response in Breast Cancer. Cancers 2018, 10, 344. https://doi.org/10.3390/cancers10100344
McGrath EP, Logue SE, Mnich K, Deegan S, Jäger R, Gorman AM, Samali A. The Unfolded Protein Response in Breast Cancer. Cancers. 2018; 10(10):344. https://doi.org/10.3390/cancers10100344
Chicago/Turabian StyleMcGrath, Eoghan P., Susan E. Logue, Katarzyna Mnich, Shane Deegan, Richard Jäger, Adrienne M. Gorman, and Afshin Samali. 2018. "The Unfolded Protein Response in Breast Cancer" Cancers 10, no. 10: 344. https://doi.org/10.3390/cancers10100344