Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Cell Proliferation and Transfection Assays
2.3. Insoluble Protein Isolation
2.4. SDS-PAGE Electrophoresis and Western Blot Hybridization
2.5. Aggresome Detection and Co-Localization Studies
2.6. Tryptic Digestion, Mass Spectrometry Analysis and Protein Identification
2.7. Statistical Analysis and Bioinformatics
2.8. Patient Sample Collection and Characterization
3. Results
3.1. Aggresome Accumulation Correlates with Reduced UPR and Autophagy Activation in Antiestrogen-Sensitive Breast Cancer Cells
3.2. Protein Aggregation after Antiestrogen Treatment Targets Different Pathways in Sensitive and Resistant Cells
3.3. Protein Aggregation after Antiestrogen Treatment Impairs Proteasome and UPR Function
3.4. Inhibition of RTCB Expression Downregulates XBP1s and Improves Sensitivity to Tamoxifen
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Uniprot IDs | Entry Name | Protein Name | Gene Names |
---|---|---|---|
TAM | |||
P42765 | THIM_HUMAN | 3-ketoacyl-CoA thiolase, mitochondrial | ACAA2 |
P22695 | QCR2_HUMAN | Cytochrome b-c1 complex subunit 2, mitochondrial | UQCRC2 |
Q9GZR7 | DDX24_HUMAN | ATP-dependent RNA helicase DDX24 | DDX24 |
P21926 | CD9_HUMAN | CD9 antigen | CD9 MIC3 TSPAN29 GIG2 |
O75607 | NPM3_HUMAN | Nucleoplasmin-3 | NPM3 |
Q96I24-1 | FUBP3_HUMAN | Far upstream element-binding protein 3 | FUBP3 FBP3 |
Q92552-2 | RT27_HUMAN | 28S ribosomal protein S27, mitochondrial | MRPS27 KIAA0264 |
Q14974 | IMB1_HUMAN | Importin subunit beta-1 | KPNB1 NTF97 |
P46087-4 | NOP2_HUMAN | Probable 28S rRNA | NOP2 NOL1 NSUN1 |
P07910-2 | HNRPC_HUMAN | Heterogeneous nuclear ribonucleoproteins C1/C2 | HNRNPC HNRPC |
Q9P0M6 | H2AW_HUMAN | Core histone macro-H2A.2 | MACROH2A2 H2AFY2 |
O00571 | DDX3X_HUMAN | ATP-dependent RNA helicase DDX3X | DDX3X DBX DDX3 |
P07741-1 | APT_HUMAN | Adenine phosphoribosyltransferase | APRT |
P31040 | SDHA_HUMAN | Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial | SDHA SDH2 SDHF |
O95793 | STAU1_HUMAN | Double-stranded RNA-binding protein Staufen homolog 1 | STAU1 STAU |
Q8WXF1 | PSPC1_HUMAN | Paraspeckle component 1 | PSPC1 PSP1 |
P19338 | NUCL_HUMAN | Nucleolin | NCL |
P30041 | PRDX6_HUMAN | Peroxiredoxin-6 | PRDX6 AOP2 KIAA0106 |
Q5SSJ5-1 | HP1B3_HUMAN | Heterochromatin protein 1-binding protein 3 | HP1BP3 |
P52943-2 | CRIP2_HUMAN | Cysteine-rich protein 2 | CRIP2 CRP2 |
Q96DI7-2 | SNR40_HUMAN | U5 small nuclear ribonucleoprotein 40 kDa protein | SNRNP40 PRP8BP SFP38 |
P06748 | NPM_HUMAN | Nucleophosmin | NPM1 NPM |
Q15233 | NONO_HUMAN | Non-POU domain-containing octamer-binding protein | NONO NRB54 |
P35659-1 | DEK_HUMAN | Protein DEK | DEK |
Q9HCD5 | NCOA5_HUMAN | Nuclear receptor coactivator 5 | NCOA5 KIAA1637 |
P62081 | RS7_HUMAN | 40S ribosomal protein S7 | RPS7 |
Q12905 | ILF2_HUMAN | Interleukin enhancer-binding factor 2 | ILF2 NF45 PRO3063 |
Q9BTV4 | TMM43_HUMAN | Transmembrane protein 43 | TMEM43 UNQ2564/PRO6244 |
P09467 | F16P1_HUMAN | Fructose-1,6-bisphosphatase 1 | FBP1 FBP |
Q15084-2 | PDIA6_HUMAN | Protein disulfide-isomerase A6 | PDIA6 ERP5 P5 TXNDC7 |
O75367-1 | H2AY_HUMAN | Core histone macro-H2A.1 | MACROH2A1 H2AFY |
Q02543 | RL18A_HUMAN | 60S ribosomal protein L18a | RPL18A |
Q15427 | SF3B4_HUMAN | Splicing factor 3B subunit 4 | SF3B4 SAP49 |
P52597 | HNRPF_HUMAN | Heterogeneous nuclear ribonucleoprotein F | HNRNPF HNRPF |
Q96GQ7 | DDX27_HUMAN | Probable ATP-dependent RNA helicase DDX27 | DDX27 cPERP-F RHLP |
Q14651 | PLSI_HUMAN | Plastin-1 | PLS1 |
Q07065 | CKAP4_HUMAN | Cytoskeleton-associated protein 4 | CKAP4 |
Q9Y3I0 | RTCB_HUMAN | RNA-splicing ligase RtcB homolog | RTCB C22orf28 HSPC117 |
P46777 | RL5_HUMAN | 60S ribosomal protein L5 | RPL5 MSTP030 |
Q9BQG0-2 | MBB1A_HUMAN | Myb-binding protein 1A | MYBBP1A P160 |
P12956 | XRCC6_HUMAN | X-ray repair cross-complementing protein 6 | XRCC6 G22P1 |
O60506 | HNRPQ_HUMAN | Heterogeneous nuclear ribonucleoprotein Q | SYNCRIP HNRPQ NSAP1 |
Q9UBU9-1 | NXF1_HUMAN | Nuclear RNA export factor 1 | NXF1 TAP |
Q9UHX1-1 | PUF60_HUMAN | Poly(U)-binding-splicing factor PUF60 | PUF60 FIR ROBPI SIAHBP1 |
P13010 | XRCC5_HUMAN | X-ray repair cross-complementing protein 5 | XRCC5 G22P2 |
P22087 | FBRL_HUMAN | rRNA 2’-O-methyltransferase fibrillarin | FBL FIB1 FLRN |
Q9NP79 | VTA1_HUMAN | Vacuolar protein sorting-associated protein VTA1 homolog | VTA1 C6orf55 HSPC228 My012 |
O76021 | RL1D1_HUMAN | Ribosomal L1 domain-containing protein 1 | RSL1D1 CATX11 CSIG PBK1 |
P36578 | RL4_HUMAN | 60S ribosomal protein L4 | RPL4 RPL1 |
P62269 | RS18_HUMAN | 40S ribosomal protein S18 | RPS18 D6S218E |
P13804-1 | ETFA_HUMAN | Electron transfer flavoprotein subunit alpha, mitochondrial | ETFA |
O43390-1 | HNRPR_HUMAN | Heterogeneous nuclear ribonucleoprotein R | HNRNPR HNRPR |
P37837 | TALDO_HUMAN | Transaldolase | TALDO1 TAL TALDO TALDOR |
P11387 | TOP1_HUMAN | DNA topoisomerase 1 | TOP1 |
ICI | |||
P27797 | CALR_HUMAN | Calreticulin | CALR CRTC |
P05386 | RLA1_HUMAN | 60S acidic ribosomal protein P1 | RPLP1 RRP1 |
Q92499 | DDX1_HUMAN | ATP-dependent RNA helicase DDX1 | DDX1 |
Q13263 | TIF1B_HUMAN | Transcription intermediary factor 1-beta | TRIM28 KAP1 RNF96 TIF1B |
P50395-1 | GDIB_HUMAN | Rab GDP dissociation inhibitor beta | GDI2 RABGDIB |
P21266 | GSTM3_HUMAN | Glutathione S-transferase Mu 3 | GSTM3 GST5 |
P62847-4 | RS24_HUMAN | 40S ribosomal protein S24 | RPS24 |
P80404 | GABT_HUMAN | 4-aminobutyrate aminotransferase, mitochondrial | ABAT GABAT |
P21964-1 | COMT_HUMAN | Catechol O-methyltransferase | COMT |
Q16643-3 | DREB_HUMAN | Drebrin | DBN1 D0S117E |
Q14258 | TRI25_HUMAN | E3 ubiquitin/ISG15 ligase TRIM25 | TRIM25 EFP RNF147 ZNF147 |
P55060-1 | XPO2_HUMAN | Exportin-2 | CSE1L CAS XPO2 |
Q9UKD2 | MRT4_HUMAN | mRNA turnover protein 4 homolog | MRTO4 C1orf33 MRT4 |
P07237 | PDIA1_HUMAN | Protein disulfide-isomerase | P4HB ERBA2L PDI PDIA1 |
P07384 | CAN1_HUMAN | Calpain-1 catalytic subunit | CAPN1 CANPL1 PIG30 |
O94826 | TOM70_HUMAN | Mitochondrial import receptor subunit TOM70 | TOMM70 KIAA0719 TOM70 |
O75955 | FLOT1_HUMAN | Flotillin-1 | FLOT1 |
P62851 | RS25_HUMAN | 40S ribosomal protein S25 | RPS25 |
P06396 | GELS_HUMAN | Gelsolin | GSN |
Q9UL46 | PSME2_HUMAN | Proteasome activator complex subunit 2 | PSME2 |
P13489 | RINI_HUMAN | Ribonuclease inhibitor | RNH1 PRI RNH |
P22314 | UBA1_HUMAN | Ubiquitin-like modifier-activating enzyme 1 | UBA1 A1S9T UBE1 |
TAM or ICI | |||
Q14257-2 | RCN2_HUMAN | Reticulocalbin-2 | RCN2 ERC55 |
P82979 | SARNP_HUMAN | SAP domain-containing ribonucleoprotein | SARNP HCC1 HSPC316 |
Q99873 | ANM1_HUMAN | Protein arginine N-methyltransferase 1 | PRMT1 HMT2 HRMT1L2 IR1B4 |
Q16181 | SEPT7_HUMAN | Septin-7 | SEPTIN7 CDC10 SEPT7 |
P41250 | GARS_HUMAN | Glycine-tRNA ligase | GARS1 GARS |
Q99832 | TCPH_HUMAN | T-complex protein 1 subunit beta | CCT7 CCTH NIP7-1 |
P17480-1 | UBF1_HUMAN | Nucleolar transcription factor 1 | UBTF UBF UBF1 |
P55735-1 | SEC13_HUMAN | Protein SEC13 homolog | SEC13 D3S1231E SEC13A |
Q96QR8 | PURB_HUMAN | Transcriptional activator protein Pur-beta | PURB |
P25787 | PSA2_HUMAN | Proteasome subunit alpha type-2 | PSMA2 HC3 PSC3 |
Q99497 | PARK7_HUMAN | Parkinson disease protein 7 | PARK7 |
Q08945 | SSRP1_HUMAN | FACT complex subunit SSRP1 | SSRP1 FACT80 |
P27824-2 | CALX_HUMAN | Calnexin | CANX |
P82650 | RT22_HUMAN | 28S ribosomal protein S22, mitochondrial | MRPS22 C3orf5 RPMS22 |
P12532 | KCRU_HUMAN | Creatine kinase U-type, mitochondrial | CKMT1A CKMT; CKMT1B |
P31939 | PUR9_HUMAN | Bifunctional purine biosynthesis protein ATIC | ATIC PURH OK/SW-cl.86 |
Q6PJT7-1 | ZC3HE_HUMAN | Zinc finger CCCH domain-containing protein 14 | ZC3H14 |
Q9BVI4 | NOC4L_HUMAN | Nucleolar complex protein 4 homolog | NOC4L |
Q8WXX5 | DNJC9_HUMAN | DnaJ homolog subfamily C member 9 | DNAJC9 |
Q9NXF1 | TEX10_HUMAN | Testis-expressed protein 10 | TEX10 L18 Nbla10363 |
O60762 | DPM1_HUMAN | Dolichol-phosphate mannosyltransferase subunit 1 | DPM1 |
Q16630-2 | CPSF6_HUMAN | Cleavage and polyadenylation specificity factor subunit 6 | CPSF6 CFIM68 |
Q86UP2-1 | KTN1_HUMAN | Kinectin | KTN1 CG1 KIAA0004 |
P49591 | SYSC_HUMAN | Serine-tRNA ligase, cytoplasmic | SARS1 SARS SERS |
Q9UN86 | G3BP2_HUMAN | Ras GTPase-activating protein-binding protein 2 | G3BP2 KIAA0660 |
Q96T37-1 | RBM15_HUMAN | RNA-binding protein 15 | RBM15 OTT OTT1 |
Q92530 | PSMF1_HUMAN | Proteasome inhibitor PI31 subunit | PSMF1 |
P23381 | SYWC_HUMAN | Tryptophan--tRNA ligase, cytoplasmic | WARS1 IFI53 WARS WRS |
Q8NE71-1 | ABCF1_HUMAN | ATP-binding cassette sub-family F member 1 | ABCF1 ABC50 |
P61353 | RL27_HUMAN | 60S ribosomal protein L27 | RPL27 |
P55084 | ECHB_HUMAN | Trifunctional enzyme subunit beta, mitochondrial | HADHB MSTP029 |
P09622 | DLDH_HUMAN | Dihydrolipoyl dehydrogenase, mitochondrial | DLD GCSL LAD PHE3 |
Q53GS9 | SNUT2_HUMAN | U4/U6.U5 tri-snRNP-associated protein 2 | USP39 CGI-21 HSPC332 |
P30101 | PDIA3_HUMAN | Protein disulfide-isomerase A3 | PDIA3 ERP57 ERP60 GRP58 |
O14579-1 | COPE_HUMAN | Coatomer subunit epsilon | COPE |
Q9UHB9 | SRP68_HUMAN | Signal recognition particle subunit SRP68 | SRP68 |
Q96EP5 | DAZP1_HUMAN | DAZ-associated protein 1 | DAZAP1 |
P17987 | TCPA_HUMAN | T-complex protein 1 subunit alpha | TCP1 CCT1 CCTA |
MCF-7 | TAM | ICI | ||
---|---|---|---|---|
Term | # Proteins | p Value | # Proteins | p Value |
hsa03010:Ribosome | 25 | 3.89 × 10−19 | 6 | 0.011 |
hsa03040:Spliceosome | 23 | 5.88 × 10−17 | 11 | 6.71 × 10−7 |
hsa03015:mRNA surveillance pathway | 6 | 0.015 | ||
hsa03050:Proteasome | 4 | 0.033 | 6 | 7.03 × 10−5 |
hsa03008:Ribosome biogenesis in eukaryotes | 5 | 0.050 | ||
hsa01130:Biosynthesis of antibiotics | 8 | 0.053 | ||
hsa03013:RNA transport | 7 | 0.057 | ||
hsa00020:Citrate cycle (TCA cycle) | 3 | 0.083 | ||
hsa00280:Valine, leucine and isoleucine degradation | 4 | 0.011 | ||
hsa01130:Biosynthesis of antibiotics | 7 | 0.019 | ||
hsa04141:Protein processing in endoplasmic reticulum | 6 | 0.027 | ||
hsa04612:Antigen processing and presentation | 4 | 0.040 | ||
MCF-7R | TAM | ICI | ||
Term | # Proteins | p Value | # Proteins | p Value |
hsa03010:Ribosome | 39 | 2.12 × 10−39 | 17 | 1.17 × 10−10 |
hsa03040:Spliceosome | 22 | 3.91 × 10−16 | 29 | 2.10 × 10−25 |
hsa03008:Ribosome biogenesis in eukaryotes | 5 | 0.045 | ||
hsa05168:Herpes simplex infection | 7 | 0.063 | 8 | 0.020 |
hsa05412:Arrhythmogenic right ventricular cardiomyopathy (ARVC) | 4 | 0.084 | ||
hsa05016:Huntington’s disease | 10 | 0.002 |
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Direito, I.; Monteiro, L.; Melo, T.; Figueira, D.; Lobo, J.; Enes, V.; Moura, G.; Henrique, R.; Santos, M.A.S.; Jerónimo, C.; et al. Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance. Cancers 2021, 13, 3195. https://doi.org/10.3390/cancers13133195
Direito I, Monteiro L, Melo T, Figueira D, Lobo J, Enes V, Moura G, Henrique R, Santos MAS, Jerónimo C, et al. Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance. Cancers. 2021; 13(13):3195. https://doi.org/10.3390/cancers13133195
Chicago/Turabian StyleDireito, Inês, Liliana Monteiro, Tânia Melo, Daniela Figueira, João Lobo, Vera Enes, Gabriela Moura, Rui Henrique, Manuel A. S. Santos, Carmen Jerónimo, and et al. 2021. "Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance" Cancers 13, no. 13: 3195. https://doi.org/10.3390/cancers13133195