GO-203 TFA is a potent MUC1-C oncoprotein inhibitor[1]. MUC1-C is an oncogenic transmembrane subunit that drives tumor survival, stemness and drug resistance by constitutively activating inflammatory and PI3K-AKT signaling pathways[2]. GO-203 TFA is an all D-amino acid peptide that consists of a poly-R transduction domain linked to a CQCRRKN motif that binds to the MUC1-C cytoplasmic tail and blocks MUC1-C homodimerization[3]. GO-203 TFA is usually used to elucidate targeted-therapy mechanisms in colorectal and other malignancies[4].
In vitro, combined treatment of U266 and RPMI8226 multiple-myeloma cells with GO-203 TFA (2.5μM; 72h) plus bortezomib synergistically lowers glutathione (GSH), raises ROS, down-regulates TP53-inducible glycolysis and apoptosis regulator (TIGAR), and drives PI/annexin-V-positive cell death[5]. Treatment of MUC1-positive SKCO-1 and COLO-205 colorectal cancer cells with GO-203 TFA (5μM; 3 days) reduced TIGAR protein, lowered GSH, doubled intracellular ROS, and collapsed mitochondrial membrane potential[6].
In vivo, GO-203 TFA (20mg/kg; i.p; 2h before each challenge on days 21, 22, 23) amplified TLR4/MyD88/NF-κB signaling, heightened NLRP3 inflammasome-mediated pyroptosis and doubled airway neutrophil counts in ovalbumin (OVA)/lipopolysaccharide (LPS)-induced asthmatic mice[7].
References:
[1] Hasegawa M, Sinha RK, Kumar M, et al. Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation. Clin Cancer Res. 2015;21(10):2338-2347.
[2] Yasumizu Y, Rajabi H, Jin C, et al. MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer. Nat Commun. 2020;11(1):338.
[3] Kharbanda A, Rajabi H, Jin C, et al. Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells. Clin Cancer Res. 2014;20(21):5423-5434.
[4] Shiba S, Miki A, Ohzawa H, et al. Functional Expression of Mucin1 in Human Duodenal Adenocarcinoma. J Surg Res. 2019;238:79-89.
[5] Yin L, Kufe T, Avigan D, Kufe D. Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death. Blood. 2014;123(19):2997-3006.
[6] Ahmad R, Alam M, Hasegawa M, et al. Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer. Mol Cancer. 2017;16(1):33.
[7] Liu L, Zhou L, Wang L, et al. MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway. Respir Res. 2023;24(1):255.
GO-203 TFA是一种强效的MUC1-C癌蛋白抑制剂[1]。MUC1-C是一种致癌跨膜亚基，通过持续激活炎症和PI3K-AKT信号通路，促进肿瘤存活、干性和耐药性[2]。GO-203 TFA是一种全D-型氨基酸肽，由聚精氨酸（poly-R）转导结构域与CQCRRKN基序连接而成，该基序可结合MUC1-C胞质尾部并阻断MUC1-C同源二聚化[3]。GO-203 TFA常用于阐明结直肠癌及其他恶性肿瘤的靶向治疗机制[4]。
体外实验中，GO-203 TFA（2.5μM; 72小时）联合硼替佐米处理U266和RPMI8226多发性骨髓瘤细胞，可协同降低谷胱甘肽（GSH）、升高活性氧（ROS）、下调TP53诱导的糖酵解与凋亡调节因子（TIGAR），并诱导PI/annexin-V阳性细胞死亡[5]。用GO-203 TFA（5μM; 3天）处理MUC1阳性SKCO-1和COLO-205结直肠癌细胞，可减少TIGAR蛋白、降低GSH、使胞内ROS翻倍，并破坏线粒体膜电位[6]。
体内实验中，GO-203 TFA（20mg/kg; 腹腔注射; 于第21、22、23天每次激发前2小时给药）可增强TLR4/MyD88/NF-κB信号通路，加剧NLRP3炎症小体介导的焦亡，并使卵清蛋白（OVA）/脂多糖（LPS）诱导的哮喘小鼠气道中性粒细胞数量翻倍[7]。