Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma.
MetadataShow full item record
AbstractMYC and HIF1α are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-TrCP-or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene. Consistent with inhibition of MYC and HIF1α, administration of echinomycin inhibited growth of lung adenocarcinoma xenograft and a syngeneic lymphoma model in mice. Furthermore, echinomycin efficiently induced regression of syngeneic mouse lymphoma driven by MYC over-expression. Our data demonstrated a new mechanism by which echinomycin simultaneously targets MYC and HIF1α for degradation to inhibit growth of lung cancer and lymphoma. Given the broad impact of β-TrCP or VHL in stability of oncogenic proteins, echinomycin may emerge as a non-PROTAC (proteolysis targeting chimera) degrader of oncogenic proteins. © 2021 by the authors.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/14750
- Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.
- Authors: Farrington CC, Yuan E, Mazhar S, Izadmehr S, Hurst L, Allen-Petersen BL, Janghorban M, Chung E, Wolczanski G, Galsky M, Sears R, Sangodkar J, Narla G
- Issue date: 2020 Jan 17
- S6K1 phosphorylation-dependent degradation of Mxi1 by β-Trcp ubiquitin ligase promotes Myc activation and radioresistance in lung cancer.
- Authors: Huang Y, Hu K, Zhang S, Dong X, Yin Z, Meng R, Zhao Y, Dai X, Zhang T, Yang K, Liu L, Huang K, Shi S, Zhang Y, Chen J, Wu G, Xu S
- Issue date: 2018
- Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas.
- Authors: Bouillez A, Rajabi H, Pitroda S, Jin C, Alam M, Kharbanda A, Tagde A, Wong KK, Kufe D
- Issue date: 2016 Mar 15
- Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma.
- Authors: Ravi D, Beheshti A, Abermil N, Passero F, Sharma J, Coyle M, Kritharis A, Kandela I, Hlatky L, Sitkovsky MV, Mazar A, Gartenhaus RB, Evens AM
- Issue date: 2016 Jun 1
- Effects of the HIF1 inhibitor, echinomycin, on growth and NOTCH signalling in leukaemia cells.
- Authors: Yonekura S, Itoh M, Okuhashi Y, Takahashi Y, Ono A, Nara N, Tohda S
- Issue date: 2013 Aug