SHP2 inhibition improves celastrol-induced growth suppression of colorectal cancer.
SHP2 inhibition improves celastrol-induced growth suppression of colorectal cancer.
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Src同源2结构域蛋白磷酸酶2（SHP2）抑制可增强雷公藤红素对结直肠癌的生长抑制作用。
DOI：
10.3389/fphar.2022.929087
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发表时间：
2022
影响因子：
5.6
通讯作者：
Pan, Yamin
中科院分区：
文献类型：
--
作者：
Zhang, Linxi;Hu, Xuefei;Meng, Qingying;Li, Ye;Shen, Hao;Fu, Yating;Zhang, Fan;Chen, Jiahui;Zhang, Wei;Chang, Wenjun;Pan, Yamin
本研究旨在基于雷公藤红素对高剂量或低剂量雷公藤红素的不同调控信号，探索雷公藤红素对结直肠癌增敏的新靶点。利用Western blotting或磷酸化受体酪氨酸激酶(RTK)阵列研究靶向信号。相应的信号抑制剂分别与小剂量雷公藤红素联合使用，以评估基于增殖、凋亡、集落分析和异种移植模型的联合抗结直肠癌效果。进一步探讨了雷公藤红素联合SHP2抑制作用的可能机制。与大剂量雷公藤红素(>；1微米)相比，低剂量雷公藤红素(<；1微米)并不能有效抑制大肠癌细胞中的AKT和ERK信号。然而，当与AKT或ERK抑制剂联合使用时，小剂量雷公藤红素可以协同抑制结直肠癌的增殖。此外，小剂量雷公藤红素抑制AKT或ERK的失败可能是由于负反馈的RTK-SHP2信号重新激活所致。联合应用雷公藤红素和SHP2抑制剂后，AKT和ERK信号显著减少，对结直肠癌生长的抑制作用强于单用雷公藤红素。此外，联合抑制的机制还涉及激活结直肠癌组织中免疫细胞(主要是CD8+细胞)的渗透。未能抑制RTK-SHP2-AKT/ERK信号通路是小剂量雷公藤红素抑制大肠癌生长的原因之一。然而，雷公藤红素和SHP2抑制剂联合应用对结直肠癌的生长有协同抑制作用，并提供了一个有希望的治疗靶点。
This study aimed to explore novel targets for celastrol sensitization in colorectal cancer (CRC) based on differentially regulated signals in response to high- or low-dose celastrol. Targeting signals were investigated using Western blotting or phosphorylated receptor tyrosine kinase (RTK) arrays. Corresponding inhibitors for the signals were individually combined with low-dose celastrol for the assessment of combined anti-CRC effects, based on proliferation, apoptosis, colony assays, and xenograft models. The potential mechanism for the combination of celastrol and SHP2 inhibition was further examined. Low-dose celastrol (<1 µM) did not effectively suppress AKT and ERK signals in CRC cells compared to high-dose celastrol (>1 µM). However, when combined with an AKT or ERK inhibitor, low-dose celastrol could cooperatively suppress CRC proliferation. Furthermore, failed AKT or ERK inhibition by low-dose celastrol may be due to reactivated RTK-SHP2 signaling with negative feedback. The combination of celastrol and the SHP2 inhibitor resulted in greatly reduced AKT and ERK signals, as well as greater inhibition of CRC growth than celastrol alone. Moreover, the mechanism underlying combination suppression was also involved in the activation of immune cell infiltration (mainly for CD8+ cells) in CRC tissues. Failure to inhibit RTK-SHP2-AKT/ERK signaling contributed to the lack of CRC growth suppression by low-dose celastrol. However, the combination of celastrol and the SHP2 inhibitor resulted in synergistic inhibition of CRC growth and provided a promising therapeutic target.
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