Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.
Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKβ, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-κB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKβ, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.
Pubmed ID: 28820388 RIS Download
Research resources used in this publication
- SW480 (RRID:CVCL_0546) (cell line)
- Crl:NU-Foxn1nu (RRID:IMSR_CRL:088) (organism)
- HCT 116 (RRID:CVCL_0291) (cell line)
- LoVo (RRID:CVCL_0399) (cell line)
- SW48 (RRID:CVCL_1724) (cell line)
- RKO (RRID:CVCL_0504) (cell line)
- LS180 (RRID:CVCL_0397) (cell line)
- SW620 (RRID:CVCL_0547) (cell line)
- DLD-1 (RRID:CVCL_0248) (cell line)
- Caco-2 (RRID:CVCL_0025) (cell line)
- SW1116 (RRID:CVCL_0544) (cell line)
- HT-29 (RRID:CVCL_0320) (cell line)
- CT26.WT (RRID:CVCL_7256) (cell line)
- Phospho-I-kappa-B-alpha (Ser32/36) (5A5) Mouse monoclonal Antibody (RRID:AB_2267145) (antibody)
- HCT 116 (RRID:CVCL_0291) (cell line)
- Caco-2 (RRID:CVCL_0025) (cell line)
- SW1116 (RRID:CVCL_0544) (cell line)
- Phospho-TAK1 (Thr184/187) (90C7) Rabbit monoclonal Antibody (RRID:AB_561317) (antibody)
- RKO (RRID:CVCL_0504) (cell line)
- LoVo (RRID:CVCL_0399) (cell line)
- Caspase-3 (8G10) Rabbit mAb (RRID:AB_2069872) (antibody)
- Mouse Anti-JNK1 / p38, phospho Monoclonal Antibody, Unconjugated, Clone 9H8 (RRID:AB_1127391) (antibody)
- Phospho-IKK-alpha (Ser176)/IKK-beta (Ser177) (C84E11) Rabbit mAb (RRID:AB_2079379) (antibody)
- Phospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (RRID:AB_331284) (antibody)
- IKK-gamma (DA10-12) Mouse mAb (RRID:AB_2124826) (antibody)
- Rabbit Anti-p53 Monoclonal Antibody, Unconjugated, Clone 7F5 (RRID:AB_10695803) (antibody)
- SW620 (RRID:CVCL_0547) (cell line)
- beta-Actin (AC-15) (RRID:AB_1119529) (antibody)
- Monoclonal ANTI-FLAG(R) antibody produced in rat (RRID:AB_10603396) (antibody)
- beta Tubulin (3F3-G2) (RRID:AB_793543) (antibody)
- Mouse Anti-GAPDH Monoclonal Antibody, Unconjugated (RRID:AB_2107299) (antibody)
- Crl:NU-Foxn1nu (RRID:IMSR_CRL:088) (organism)
- PARP (46D11) Rabbit mAb (RRID:AB_659884) (antibody)
- Goat Anti-NF kappa B p65 Polyclonal antibody, Unconjugated (RRID:AB_632037) (antibody)
- GST (56C1) (RRID:AB_1124757) (antibody)
- SW48 (RRID:CVCL_1724) (cell line)
- DLD-1 (RRID:CVCL_0248) (cell line)
- LS180 (RRID:CVCL_0397) (cell line)
- CT26.WT (RRID:CVCL_7256) (cell line)
- NFkappaB p50 (NLS) (RRID:AB_632034) (antibody)
- PKR (D7F7) Rabbit mAb #12297 (RRID:AB_2665515) (antibody)
- IKK-beta (2C8) Rabbit mAb (RRID:AB_2122154) (antibody)
- SW480 (RRID:CVCL_0546) (cell line)
- TAK1 (D94D7) Rabbit mAb (RRID:AB_10694079) (antibody)
- HT-29 (RRID:CVCL_0320) (cell line)
- JNK (D-2) (RRID:AB_675864) (antibody)
- NF-κB1 p105/p50 (D4P4D) Rabbit mAb #13586 (RRID:AB_2665516) (antibody)
Additional research tools detected in this publication
Antibodies used in this publication
- Mouse Anti-JNK1 / p38, phospho Monoclonal Antibody, Unconjugated, Clone 9H8 (RRID:AB_1127391)
- beta-Actin (AC-15) (RRID:AB_1119529)
- PARP (46D11) Rabbit mAb (RRID:AB_659884)
- IKK-gamma (DA10-12) Mouse mAb (RRID:AB_2124826)
- Phospho-IKK-alpha (Ser176)/IKK-beta (Ser177) (C84E11) Rabbit mAb (RRID:AB_2079379)
- Goat Anti-NF kappa B p65 Polyclonal antibody, Unconjugated (RRID:AB_632037)
- Caspase-3 (8G10) Rabbit mAb (RRID:AB_2069872)
- IKK-beta (2C8) Rabbit mAb (RRID:AB_2122154)
- JNK (D-2) (RRID:AB_675864)
- Rabbit Anti-p53 Monoclonal Antibody, Unconjugated, Clone 7F5 (RRID:AB_10695803)
- NFkappaB p50 (NLS) (RRID:AB_632034)
- PKR (D7F7) Rabbit mAb #12297 (RRID:AB_2665515)
- TAK1 (D94D7) Rabbit mAb (RRID:AB_10694079)
- Phospho-TAK1 (Thr184/187) (90C7) Rabbit monoclonal Antibody (RRID:AB_561317)
- NF-κB1 p105/p50 (D4P4D) Rabbit mAb #13586 (RRID:AB_2665516)
- beta Tubulin (3F3-G2) (RRID:AB_793543)
- Phospho-I-kappa-B-alpha (Ser32/36) (5A5) Mouse monoclonal Antibody (RRID:AB_2267145)
- Monoclonal ANTI-FLAG(R) antibody produced in rat (RRID:AB_10603396)
- Mouse Anti-GAPDH Monoclonal Antibody, Unconjugated (RRID:AB_2107299)
- GST (56C1) (RRID:AB_1124757)
- Phospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (RRID:AB_331284)
Associated grants
NonePublication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
ATCC (tool)
RRID:SCR_001672
Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.
View all literature mentionsPlantCyc (tool)
RRID:SCR_002110
Multi species reference database. Comprehensive plant biochemical pathway database, containing curated information from literature and computational analyses about genes, enzymes, compounds, reactions, and pathways involved in primary and secondary metabolism.
View all literature mentionsKEGG (tool)
RRID:SCR_012773
Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.
View all literature mentionsBio-Rad Laboratories (tool)
RRID:SCR_008426
Commercial instrument and chemical vendor. Developer and manufacturer of specialized technological products for life science research and clinical diagnostics markets.
View all literature mentionsBALB/cAnNCrl (tool)
RRID:MGI:2683685
laboratory mouse with name BALB/cAnNCrl from MGI.
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RRID:AB_1127391
This monoclonal targets MAPK8, MAPK9, MAPK10
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RRID:AB_1119529
This monoclonal targets beta-Actin (AC-15)
View all literature mentionsPARP (46D11) Rabbit mAb (antibody)
RRID:AB_659884
This monoclonal targets PARP
View all literature mentionsIKK-gamma (DA10-12) Mouse mAb (antibody)
RRID:AB_2124826
This monoclonal targets IKBKG
View all literature mentionsPhospho-IKK-alpha (Ser176)/IKK-beta (Ser177) (C84E11) Rabbit mAb (antibody)
RRID:AB_2079379
This monoclonal targets CHUK
View all literature mentionsGoat Anti-NF kappa B p65 Polyclonal antibody, Unconjugated (antibody)
RRID:AB_632037
This polyclonal targets RELA
View all literature mentionsCaspase-3 (8G10) Rabbit mAb (antibody)
RRID:AB_2069872
This monoclonal targets Caspase-3 (8G10) Rabbit mAb
View all literature mentionsIKK-beta (2C8) Rabbit mAb (antibody)
RRID:AB_2122154
This monoclonal targets Ikbkb
View all literature mentionsRabbit Anti-p53 Monoclonal Antibody, Unconjugated, Clone 7F5 (antibody)
RRID:AB_10695803
This monoclonal targets p53
View all literature mentionsNFkappaB p50 (NLS) (antibody)
RRID:AB_632034
This polyclonal targets NFKB1
View all literature mentionsPKR (D7F7) Rabbit mAb #12297 (antibody)
RRID:AB_2665515
This monoclonal targets PKR
View all literature mentionsTAK1 (D94D7) Rabbit mAb (antibody)
RRID:AB_10694079
This monoclonal targets TAK1 (D94D7) Rabbit mAb
View all literature mentionsPhospho-TAK1 (Thr184/187) (90C7) Rabbit monoclonal Antibody (antibody)
RRID:AB_561317
This monoclonal targets Phospho-TAK1 (Thr184/187)
View all literature mentionsNF-κB1 p105/p50 (D4P4D) Rabbit mAb #13586 (antibody)
RRID:AB_2665516
This monoclonal targets NF-κB1
View all literature mentionsbeta Tubulin (3F3-G2) (antibody)
RRID:AB_793543
This monoclonal targets TUBB
View all literature mentionsPhospho-I-kappa-B-alpha (Ser32/36) (5A5) Mouse monoclonal Antibody (antibody)
RRID:AB_2267145
This monoclonal targets IkappaB-alpha, phospho (Ser32 / Ser36)
View all literature mentionsMonoclonal ANTI-FLAG(R) antibody produced in rat (antibody)
RRID:AB_10603396
This monoclonal targets ANTI-FLAG(R) antibody produced in rat
View all literature mentionsMouse Anti-GAPDH Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2107299
This monoclonal targets Gapdh
View all literature mentionsGST (56C1) (antibody)
RRID:AB_1124757
This monoclonal targets GST (56C1)
View all literature mentionsPhospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (antibody)
RRID:AB_331284
This monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsSW480 (cell line)
RRID:CVCL_0546
Cell line SW480 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCrl:NU-Foxn1nu (organism)
RRID:IMSR_CRL:088
Mus musculus with name Crl:NU-Foxn1nu from IMSR.
View all literature mentionsHCT 116 (cell line)
RRID:CVCL_0291
Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLoVo (cell line)
RRID:CVCL_0399
Cell line LoVo is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSW48 (cell line)
RRID:CVCL_1724
Cell line SW48 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRKO (cell line)
RRID:CVCL_0504
Cell line RKO is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLS180 (cell line)
RRID:CVCL_0397
Cell line LS180 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSW620 (cell line)
RRID:CVCL_0547
Cell line SW620 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDLD-1 (cell line)
RRID:CVCL_0248
Cell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCaco-2 (cell line)
RRID:CVCL_0025
Cell line Caco-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSW1116 (cell line)
RRID:CVCL_0544
Cell line SW1116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHT-29 (cell line)
RRID:CVCL_0320
Cell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCT26.WT (cell line)
RRID:CVCL_7256
Cell line CT26.WT is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsPhospho-I-kappa-B-alpha (Ser32/36) (5A5) Mouse monoclonal Antibody (antibody)
RRID:AB_2267145
This monoclonal targets IkappaB-alpha, phospho (Ser32 / Ser36)
View all literature mentionsHCT 116 (cell line)
RRID:CVCL_0291
Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCaco-2 (cell line)
RRID:CVCL_0025
Cell line Caco-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSW1116 (cell line)
RRID:CVCL_0544
Cell line SW1116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPhospho-TAK1 (Thr184/187) (90C7) Rabbit monoclonal Antibody (antibody)
RRID:AB_561317
This monoclonal targets Phospho-TAK1 (Thr184/187)
View all literature mentionsRKO (cell line)
RRID:CVCL_0504
Cell line RKO is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLoVo (cell line)
RRID:CVCL_0399
Cell line LoVo is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCaspase-3 (8G10) Rabbit mAb (antibody)
RRID:AB_2069872
This monoclonal targets Caspase-3 (8G10) Rabbit mAb
View all literature mentionsMouse Anti-JNK1 / p38, phospho Monoclonal Antibody, Unconjugated, Clone 9H8 (antibody)
RRID:AB_1127391
This monoclonal targets MAPK8, MAPK9, MAPK10
View all literature mentionsPhospho-IKK-alpha (Ser176)/IKK-beta (Ser177) (C84E11) Rabbit mAb (antibody)
RRID:AB_2079379
This monoclonal targets CHUK
View all literature mentionsPhospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (antibody)
RRID:AB_331284
This monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsIKK-gamma (DA10-12) Mouse mAb (antibody)
RRID:AB_2124826
This monoclonal targets IKBKG
View all literature mentionsRabbit Anti-p53 Monoclonal Antibody, Unconjugated, Clone 7F5 (antibody)
RRID:AB_10695803
This monoclonal targets p53
View all literature mentionsSW620 (cell line)
RRID:CVCL_0547
Cell line SW620 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsbeta-Actin (AC-15) (antibody)
RRID:AB_1119529
This monoclonal targets beta-Actin (AC-15)
View all literature mentionsMonoclonal ANTI-FLAG(R) antibody produced in rat (antibody)
RRID:AB_10603396
This monoclonal targets ANTI-FLAG(R) antibody produced in rat
View all literature mentionsbeta Tubulin (3F3-G2) (antibody)
RRID:AB_793543
This monoclonal targets TUBB
View all literature mentionsMouse Anti-GAPDH Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2107299
This monoclonal targets Gapdh
View all literature mentionsCrl:NU-Foxn1nu (organism)
RRID:IMSR_CRL:088
Mus musculus with name Crl:NU-Foxn1nu from IMSR.
View all literature mentionsPARP (46D11) Rabbit mAb (antibody)
RRID:AB_659884
This monoclonal targets PARP
View all literature mentionsGoat Anti-NF kappa B p65 Polyclonal antibody, Unconjugated (antibody)
RRID:AB_632037
This polyclonal targets RELA
View all literature mentionsGST (56C1) (antibody)
RRID:AB_1124757
This monoclonal targets GST (56C1)
View all literature mentionsSW48 (cell line)
RRID:CVCL_1724
Cell line SW48 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDLD-1 (cell line)
RRID:CVCL_0248
Cell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLS180 (cell line)
RRID:CVCL_0397
Cell line LS180 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCT26.WT (cell line)
RRID:CVCL_7256
Cell line CT26.WT is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsNFkappaB p50 (NLS) (antibody)
RRID:AB_632034
This polyclonal targets NFKB1
View all literature mentionsPKR (D7F7) Rabbit mAb #12297 (antibody)
RRID:AB_2665515
This monoclonal targets PKR
View all literature mentionsIKK-beta (2C8) Rabbit mAb (antibody)
RRID:AB_2122154
This monoclonal targets Ikbkb
View all literature mentionsSW480 (cell line)
RRID:CVCL_0546
Cell line SW480 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsTAK1 (D94D7) Rabbit mAb (antibody)
RRID:AB_10694079
This monoclonal targets TAK1 (D94D7) Rabbit mAb
View all literature mentionsHT-29 (cell line)
RRID:CVCL_0320
Cell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNF-κB1 p105/p50 (D4P4D) Rabbit mAb #13586 (antibody)
RRID:AB_2665516
This monoclonal targets NF-κB1
View all literature mentions
