Intracellular MUC1 Peptides Inhibit Cancer Progression
Intracellular MUC1 Peptides Inhibit Cancer Progression
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DOI：
10.1158/1078-0432.ccr-08-1745
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发表时间：
2009-01-01
影响因子：
11.5
通讯作者：
Schroeder, Joyce A.
中科院分区：
文献类型：
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作者：
Bitler, Benjamin G.;Menzl, Ina;Schroeder, Joyce A.
目的：在肿瘤进展过程中，癌蛋白MUC1与p-catenin结合，同时抑制表皮生长因子受体（epidermal growth factor receptor， EGFR）的降解，导致转化和转移增强。本研究的目的是设计一种基于肽的治疗方法，以阻断细胞内蛋白质-蛋白质相互作用，作为转移性乳腺癌的治疗方法。实验设计：负责这些相互作用的氨基酸残基串联在MUC1的细胞质结构域中，我们针对这一序列生产了一种MUC1肽，该肽可阻断MUC1的致蛋白功能。我们设计了MUC1抑制肽（MIP）来阻断MUC1/ β -连环蛋白和MUC1/EGFR之间的细胞内相互作用。为了允许细胞摄取，我们在蛋白质转导结构域PTD4 （PMIP）附近合成了MIP。结果：我们发现PMIP以显性负性方式起作用，阻断MUC1/ β -连环蛋白和MUCI/EGFR相互作用。此外，PMIP诱导EGFR水平的配体依赖性降低。这些作用对应于在体外显著减少转移性乳腺癌细胞的增殖、迁移和侵袭，以及在已建立的MDA-MB-231免疫功能低下（SCID）小鼠模型中抑制肿瘤生长和复发。重要的是，PMIP还可以抑制遗传驱动的乳腺癌进展，因为注射带有PMIP的荷瘤MMTV-pyV mT转基因小鼠可导致肿瘤消退并显著抑制肿瘤生长速度。结论：细胞内MUC1肽具有显著的抗肿瘤活性，在肿瘤治疗中具有重要的临床应用价值。
Purpose: During cancer progression, the oncoprotein MUC1 binds p-catenin while simultaneously inhibiting the degradation of the epidermal growth factor receptor (EGFR), resulting in enhanced transformation and metastasis. The purpose of this study was to design a peptide-based therapy that would block these intracellular protein-protein interactions as a treatment for metastatic breast cancer.Experimental Design: The amino acid residues responsible for these interactions lie in tandem in the cytoplasmic domain of MUC1, and we have targeted this sequence to produce a MUC1 peptide that blocks the protumorigenic functions of MUC1. We designed the MUC1 inhibitory peptide (MIP) to block the intracellular interactions between MUC1/beta-catenin and MUC1/EGFR. To allow for cellular uptake we synthesized MIP adjacent to the protein transduction domain, PTD4 (PMIP).Results: We have found that PMIP acts in a dominant-negative fashion, blocking both MUC1/beta-catenin and MUCI/EGFR interactions. In addition, PMIP induces ligand-dependent reduction of EGFR levels. These effects correspond to a significant reduction in proliferation, migration, and invasion of metastatic breast cancer cells in vitro, and inhibition of tumor growth and recurrence in an established MDA-MB-231 immunocompromised (SCID) mouse model. Importantly, PMIP also inhibits genetically driven breast cancer progression, as injection of tumor-bearing MMTV-pyV mT transgenic mice with PMIP results in tumor regression and a significant inhibition of tumor growth rate.Conclusions: These data show that intracellular MUC1 peptides possess significant antitumor activity and have important clinical applications in the treatment of cancer.