Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors
Abstract
:1. Introduction
2. The Introduction of TP53 and Tumor Suppressive Role of p53
2.1. The Finding of TP53
2.2. The Functional Role of Wild Type p53
3. TP53 Mutation in CRC and Other Solid Tumors
3.1. TP53 Mutational Spectrum in CRC
3.2. The Mechanisms of p53 Mutants with Gain of Fucntion (GOF)
3.3. Oncogenic Roles of p53 Mutants with GOF
3.3.1. Enhancing Cell Proliferation and Colony Formation
3.3.2. Promoting Migration, Invasion and Metastasis
3.3.3. Inducing Angiogenesis
3.3.4. Inducing Chromatin Remodeling
4. Targeting p53 Mutants in Tumorigenicity
4.1. Restoring the Function of Wild Type p53
4.1.1. Cysteine-Binding Compounds
4.1.2. Zn2+-Chelating Compounds
4.1.3. Peptides
4.1.4. Other Types of Compounds
4.2. Depleting Mutated p53 Proteins
4.3. Inducing Synthetic Lethality to p53 Mutants
4.4. Targeting the Oncogenic Downstreams of p53 Mutants
5. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Mutation Type | Cell Lines | Downstream Effectors | Refs |
---|---|---|---|
Promoting cell proliferation | |||
R273H | U373/SNB19 | c-Myc/Bcl-XL | [40] |
R280K/R282W | MDA-MB-231/MDA-MB-1386 | KLF17 | [46] |
R273H | H1299 | miR-27a/EGFR | [47] |
R273H/R175H/D281G | H1299 | Axl | [48] |
R273C/R267P | H1048/H1437 | ||
R238Q/R172H | - | HSP90/HDAC6 | [49] |
R249S/R273L/R280K | BT549/HCC38/MDAMB231 | EST2/NMGs | [50] |
R249S/R175H | MCF10a/H1299 | ||
R248Q | HEC-1B | REG-γ | [51] |
R175H | H1299/UMSCC-1 | REG-γ | [52] |
R280K/R282W/R273H | MDA-MB-231/MDA-MB-1386 | ||
P278S/R267P | ABC1/H1437 | Axl | [78] |
R175H/R273H | H1299 | TopBP1 | [54] |
R273C/R248Q/R175H | C33A/OVCAR-3/SKBr3 | ||
R175H/R273H/R280K | SKBR3/HT29/MDA-MB468/MDA-MB231 | MAP2K3 | [79] |
R280T | SWO-38 | GSK-3β/PTEN | [80] |
R280K/R273H | MDA-MB-231/MDA-468 | SREBPs | [64] |
Increasing colony formation ability | |||
R273H | U373/SNB19 | c-Myc/Bcl-XL | [40] |
R273H | H1299 | NRF2 | [53] |
R175H/R273H | H1299 | TopBP1 | [54] |
R273C/R248Q/R175H | C33A/OVCAR-3/SKBr3 | ||
R273H | MCF10a | HSF1 | [55] |
R273H | H1299 | miR-27a/EGFR | [47] |
R175H | HCT116-/- | GRO1 | [56] |
R273H/P309S | SW480 | ||
R248W | MIA-PaCa-2 | ||
Increasing cell invasion and migration | |||
R273H | U373/SNB19 | c-Myc/Bcl-XL | [40] |
R280K/R282W | MDA-MB-231/MDA-MB-1386 | KLF17 | [46] |
R249S/R273L/R280K | BT549/HCC38/MDAMB231 | EST2/NMGs | [50] |
R249S/R175H | MCF10a/H1299 | ||
R248Q | HEC-1B | REG-γ | [51] |
R175H/R273H | MCF10a/H1299 | RCP/integrin/EGFR | [60] |
R273H | H1299 | TAp63/Dicer | [61] |
R280K/R273H | MDA-MB-231/HT29/A431 | ||
R175H/R273H | H1299 | TAp63/Met | [62] |
R175H | H1299 | TAp63/Sharp 1/Cyclin G2 | [41] |
R175H | H1299 | Smad3 | [42] |
R175H | H1299 | let-7i/E2F5/LIN28B/MYC | [59] |
R248W/R220C/H242R/H155P | Miapaca2/BXPC3/CFPAC/A2.1 | p73/NF-Y/PDGFR-beta | [63] |
R273H/R280K | SW620/H1975/MDA-MB-231 | ||
R280K/R273H | MDA-MB-231/MDA-468 | SREBPs | [64] |
R280K | MDA-MB-231 | Myo10 | [65] |
R175H/R273H/C135Y | HEC-50 | miR-130b/ZEB1 | [58] |
R273H | U373/SNB19 | c-Myc/Bcl-XL | [40] |
R280K | MDA-MB-231 | KLF17 | [46] |
R282W | MDA-MB-1386 | ||
R273H/R175H/D281G | H1299 | Axl | [48] |
R273C/R267P | H1048/H1437 | ||
R175H | H1299 | TAp63/Sharp 1/Cyclin G2 | [41] |
R175H | H1299 | let-7i/E2F5/LIN28B/MYC | [59] |
R175H/R273H/D281G | H1299 | CXCL5/CXCL8/CXCL12 | [57] |
R280K | MDA-MB-231 | Pin1 | [81] |
Inducing angiogenesis | |||
R175H/R273H/R248W | HCT116-/- | HIF1/VEGF-A | [68] |
R175H/R273H | H1299 | ID4/IL8/GRO-a | [71] |
R280K | MDA-MB-231 | ||
Chromatin remodeling | |||
R248Q | HCC70 | MLL1/MLL2/MOZ | [73] |
R249S | BT-549 | ||
R273H | MDA-MB-468 | ||
R273H | SW480 | MMP9/CCL2/CYP24A1/CPA4 | [74] |
R273H | MDA-468 | VEGFR2/SWI/SNF | [72] |
Reactivating the Wild Type p53 Function | |||
---|---|---|---|
Compounds (Small Molecules) | Mechanisms | Clinical Trial (Cancers) | Refs. |
Cysteine-binding compounds | |||
CP-31398 | binds to the cysteine residues | [85,86,87,88] | |
PRIMA-1 | converts to methylene quinuclidinone | [89,90,91,92] | |
APR-246 | converts to methylene quinuclidinone | phase Ib/II (lymphoma, ovarian, esophageal) | [90,91,92,93,94] |
MIRA-1 | prevents unfolding of wild-type and mutant p53 | [98] | |
STIMA-1 | prevents unfolding of wild-type and mutant p53 | [99] | |
KSS-9 | prevents unfolding of wild-type and mutant p53 | [100] | |
PK11007 | binds p53 by nucleophilic aromatic substitution | [101] | |
3-Benzoylacrylic acid | binds p53 by Michael addition | [102] | |
Zn2+-chelating compounds | |||
ZMC-1 | Zn2+ chelator | [104] | |
COTI-2 | Zn2+ chelator | phase I (gynecological, head and neck cancer) | [105] |
Peptides | |||
pCAPs | promote refolding | [107] | |
Reacp53 | blocks aggregation | [108] | |
Other types of compounds | |||
PK083 | restores wild-type conformation | [109] | |
PK7088 | restores wild-type conformation | [105] | |
P53R3 | restores DNA-binding ability | [106] | |
SCH529074 | restores DNA-binding ability | [112] | |
Chetomin | promotes refolding | [113] | |
RETRA | disrupts mutant p53–p73 complexes | [114] | |
Depleting the GOF of p53 mutants | |||
17AAG | Hsp90 inhibitors | [116] | |
Ganetespib | Hsp90 inhibitors | phase III (lung cancer) | [49] |
SAHA | HDAC inhibitors | [117] | |
Arsenic compounds | increases transcripts of Pirh2,and | [118] | |
induces degradation of mutant p53 | [119] | ||
Gambogic acid | inhibits the mutant p53-Hsp90 complex | [121] | |
Spautin-1 | induces mutant p53 degradation | [122] | |
YK-3-237 | activates SIRT1 and deacetylate lysine 382 | [123] | |
NSC59984 | induces MDM2-mediated mutant p53 degradation | [124] | |
Disulfiram | induces p53 degradation | [125] | |
Inducing synthetic lethality | |||
UCN01 | protein kinase C inhibitor | [126] | |
BI-2536 | polo-like kinase 1 inhibitor | [127] | |
PD0166285 | Wee1 kinase inhibitor | [128] | |
Blocking the oncogenic downstreams of p53 mutants | |||
Statins | HMG-CoA reductase inhibitor | [64] | |
inhibits YAP/TAZ activation | [129] |
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Li, H.; Zhang, J.; Tong, J.H.M.; Chan, A.W.H.; Yu, J.; Kang, W.; To, K.F. Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors. Int. J. Mol. Sci. 2019, 20, 5999. https://doi.org/10.3390/ijms20235999
Li H, Zhang J, Tong JHM, Chan AWH, Yu J, Kang W, To KF. Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors. International Journal of Molecular Sciences. 2019; 20(23):5999. https://doi.org/10.3390/ijms20235999
Chicago/Turabian StyleLi, Hui, Jinglin Zhang, Joanna Hung Man Tong, Anthony Wing Hung Chan, Jun Yu, Wei Kang, and Ka Fai To. 2019. "Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors" International Journal of Molecular Sciences 20, no. 23: 5999. https://doi.org/10.3390/ijms20235999