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莪术醇靶向OTUB1/TGFBI泛素化途径抑制结肠癌血管生成的机制

Mechanism of Curcumol Targeting the OTUB1/TGFBI Ubiquitination Pathway in the Inhibition of Angiogenesis in Colon Cancer.

作者信息

Zhu Yimiao, Wu Wenya, Hou Dahai, Zhao Yu, Ye Jinshu, Shen Lizong, Zhao Tong, Wu Xiaoyu

机构信息

First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210046, China.

School of Integrated Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.

出版信息

Int J Mol Sci. 2025 May 21;26(10):4899. doi: 10.3390/ijms26104899.

DOI:10.3390/ijms26104899
PMID:40430059
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12112734/
Abstract

Tumor angiogenesis and metastasis are critical processes in the progression of colon carcinoma. Curcumol, a bioactive sesquiterpenoid derived from curcuma, exhibits anti-angiogenic properties, though its underlying mechanisms remain unclear. In this study, an HT-29 xenograft mouse model demonstrated that curcumol combined with oxaliplatin significantly suppressed tumor growth (Ki67↓) and microvessel density (CD31↓). In vitro assays revealed that curcumol dose dependently inhibited proliferation (MTT), migration (Transwell), and tube formation (CAM assay) in Caco-2/HT-29 and HUVEC cells. Mechanistically, curcumol downregulated OTUB1 expression, promoting TGFB1 degradation via the ubiquitin-proteasome pathway. OTUB1 overexpression activated the TGFB1/VEGF axis, enhancing cell invasiveness and angiogenesis-effects reversed by high-dose curcumol. These findings identify the OTUB1-TGFB1/VEGF axis as a key target of curcumol in inhibiting colon cancer angiogenesis, elucidating its anti-tumor mechanism and offering a novel therapeutic strategy for targeted treatment.

摘要

肿瘤血管生成和转移是结肠癌进展中的关键过程。莪术醇是一种从姜黄中提取的具有生物活性的倍半萜类化合物，具有抗血管生成特性，但其潜在机制尚不清楚。在本研究中，HT-29异种移植小鼠模型表明，莪术醇联合奥沙利铂可显著抑制肿瘤生长（Ki67降低）和微血管密度（CD31降低）。体外试验显示，莪术醇剂量依赖性地抑制Caco-2/HT-29和HUVEC细胞的增殖（MTT法）、迁移（Transwell法）和管腔形成（鸡胚绒毛尿囊膜试验）。机制上，莪术醇下调OTUB1表达，通过泛素-蛋白酶体途径促进TGFB1降解。OTUB1过表达激活TGFB1/VEGF轴，增强细胞侵袭性和血管生成作用，高剂量莪术醇可逆转这些作用。这些发现确定OTUB1-TGFB1/VEGF轴是莪术醇抑制结肠癌血管生成的关键靶点，阐明了其抗肿瘤机制，并为靶向治疗提供了一种新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/c4e700d4eef0/ijms-26-04899-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/ae9849de1884/ijms-26-04899-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/23dfdcebeacd/ijms-26-04899-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/69b7ce88eb78/ijms-26-04899-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/b0edb8e0334d/ijms-26-04899-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/4eda057028dc/ijms-26-04899-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/d7e777aa722b/ijms-26-04899-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/ef65991a8643/ijms-26-04899-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/c4e700d4eef0/ijms-26-04899-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/ae9849de1884/ijms-26-04899-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/23dfdcebeacd/ijms-26-04899-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/69b7ce88eb78/ijms-26-04899-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/b0edb8e0334d/ijms-26-04899-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/4eda057028dc/ijms-26-04899-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/d7e777aa722b/ijms-26-04899-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/ef65991a8643/ijms-26-04899-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3167/12112734/c4e700d4eef0/ijms-26-04899-g008.jpg

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引用本文的文献

[1]
The effect of ubiquitination and deubiquitination to imatinib resistance in gastrointestinal stromal tumors.

Front Oncol. 2025-7-25

本文引用的文献

[1]
TGFBI promotes proliferation and epithelial-mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR/HIF-1α pathway.

Cancer Cell Int. 2024-7-27

[2]
TGFBI: A novel therapeutic target for cancer.

Int Immunopharmacol. 2024-6-15

[3]
Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of β-catenin.

J Transl Med. 2024-2-24

[4]
VEGF signaling: Role in angiogenesis and beyond.

Biochim Biophys Acta Rev Cancer. 2024-3

[5]
OTUB1 Targets CHK1 for Deubiquitination and Stabilization to Facilitate Lung Cancer Progression and Radioresistance.

Int J Radiat Oncol Biol Phys. 2024-7-15

[6]
OTUB1-mediated inhibition of ubiquitination: a growing list of effectors, multiplex mechanisms, and versatile functions.

Front Mol Biosci. 2024-1-9

[7]
Colorectal cancer: a comprehensive review of carcinogenesis, diagnosis, and novel strategies for classified treatments.

Cancer Metastasis Rev. 2024-6

[8]
Icariin-Curcumol promotes docetaxel sensitivity in prostate cancer through modulation of the PI3K-Akt signaling pathway and the Warburg effect.

Cancer Cell Int. 2023-9-2

[9]
OTUB1 inhibits breast cancer by non-canonically stabilizing CCN6.

Clin Transl Med. 2023-8

[10]
Normalization of Tumor Vessels by Lenvatinib-Based Metallo-Nanodrugs Alleviates Hypoxia and Enhances Calreticulin-Mediated Immune Responses in Orthotopic HCC and Organoids.

Small. 2023-7

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