A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer
A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer
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PROTAC 肽可诱导持久的 β-连环蛋白降解并抑制 Wnt 依赖性肠癌
DOI：
10.1038/s41421-020-0171-1
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发表时间：
2020-06-09
期刊：
影响因子：
33.5
通讯作者：
Chen, Ye-Guang
中科院分区：
文献类型：
--
作者：
Liao, Hongwei;Li, Xiang;Chen, Ye-Guang
Wnt/ β -catenin信号的异常激活与许多类型肿瘤的发生和进展有关，因此β -catenin是癌症治疗的一个有吸引力的细胞内靶点。基于轴蛋白衍生肽结合β -catenin，两种钉接肽SAHPA1和xStAx分别增强或损害Wnt/ β -catenin信号传导。在这项研究中，我们通过将SAHPA1或xStAx与VHL配体偶联来设计PROTACs（蛋白水解靶向嵌合体），以实现高效的β -连环蛋白降解。获得的xStAx-VHLL持续β -连环蛋白降解，并在癌细胞和APC（-/-）类器官中表现出强烈的Wnt信号抑制作用。此外，xStAx-VHLL能有效抑制BALB/C裸鼠的肿瘤形成，减少APC（min/+）小鼠的肿瘤存在。更重要的是，xStAx-VHLL可以有效地抑制结直肠癌患者来源的类器官的存活。这些发现表明，xStAx-VHLL具有癌症预防和治疗的能力，突出了β -连环蛋白降解物PROTACs作为一类新的抗癌药物的潜力。
Aberrant activation of Wnt/beta-catenin signaling has been associated with the onset and progression of many types of tumors and thus beta-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to beta-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/beta-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient beta-catenin degradation. The obtained xStAx-VHLL sustained beta-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC(-/-) organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC(min/+) mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patient-derived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of beta-catenin degrader PROTACs as a new class of promising anticancer agent.