Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma.
Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma.
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DOI：
10.3390/cancers13040694
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发表时间：
2021-02-09
期刊：
影响因子：
5.2
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Huang X;Liu Y;Wang Y;Bailey C;Zheng P;Liu Y
MYC和HIF 1 α都是参与多种人类肿瘤的启动、转化、进展和维持的关键转录因子，但目前尚无研究表明是否可能同时靶向MYC和HIF 1 α进行治疗。在这里，我们报告棘霉素通过蛋白酶体降解同时抑制MYC和HIF 1 α。在体外培养的细胞和体内肺癌和淋巴瘤小鼠模型中，棘霉素治疗均使肿瘤细胞生长消退。β-TrCP和VHL分别参与了棘霉素诱导的MYC和HIF 1 α的降解。我们的数据提供了一种新的方法来靶向这些和潜在的其他致癌蛋白的癌症治疗。MYC和HIF 1 α是最重要的癌蛋白之一，其药理学抑制一直具有挑战性，因为驱动其异常表达的多种机制以及阻断蛋白质-DNA相互作用的挑战。令人惊讶的是，我们发现棘霉素处理的细胞中的MYC和HIF 1 α蛋白通过蛋白酶体依赖性途径降解，分别通过β-TrCP或VHL依赖性机制降解。在多种癌症类型中诱导降解，包括在p53肿瘤和LKB肿瘤抑制因子和KRAS癌基因中具有突变的那些。与MYC和HIF 1 α的抑制一致，棘霉素给药抑制了小鼠肺腺癌异种移植物和同基因淋巴瘤模型的生长。此外，棘霉素有效地诱导由MYC过表达驱动的同基因小鼠淋巴瘤的消退。我们的数据证明了棘霉素同时靶向MYC和HIF 1 α降解以抑制肺癌和淋巴瘤生长的新机制。鉴于β-TrCP或VHL对致癌蛋白稳定性的广泛影响，棘霉素可能作为致癌蛋白的非PROTAC（蛋白水解靶向嵌合体）降解剂出现。
Both MYC and HIF1α are critical transcriptional factors involved in the initiation, transformation, progression and maintenance in a variety of human tumors, but till now no study indicates whether it is possible to simultaneously targeting both MYC and HIF1α for therapeutics. Here we report that echinomycin simultaneously inhibited MYC and HIF1α through proteasomal degradation. Treatment of echinomycin regressed tumor cell growth both in vitro cultured cells and in vivo mouse models of lung cancer and lymphoma. β-TrCP and VHL are involved in the degradation of MYC and HIF1α induced by echinomycin, respectively. Our data provided a new approach to target these and potentially other oncogenic proteins for cancer therapy. MYC 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.
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影响因子：
4.8
作者：
Hoffmann, Andreas-Claudius;Mori, Ryutaro;Danenberg, Peter V.
通讯作者：
Danenberg, Peter V.
DOI：
10.1007/s12032-014-0877-8
发表时间：
2014-04
期刊：
Medical oncology (Northwood, London, England)
影响因子：
--
作者：
Liu B;Liu Q;Song Y;Li X;Wang Y;Wan S;Zhang Z;Su H
通讯作者：
Su H
DOI：
10.1073/pnas.0808042106
发表时间：
2009-03-03
影响因子：
11.1
作者：
Sachdeva, Mohit;Zhu, Shoumin;Mo, Yin-Yuan
通讯作者：
Mo, Yin-Yuan
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
4.7
作者：
Jung, Seung-Nam;Yang, Woo Kyeom;Ha, Joohun
通讯作者：
Ha, Joohun