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Decylubiquinone Inhibits Colorectal Cancer Growth Through Upregulating Sirtuin2.

ABSTRACT: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Decylubiquinone (DUb), a coenzyme Q10 analog, was reported to inhibit breast cancer growth and metastasis by us. However, the influence of DUb on CRC remains unclear. Herein, we found that DUb significantly inhibited CRC growth in the patient-derived xenograft (PDX) and CT26 xenograft models. DUb was further identified to significantly suppress CRC cell proliferation, colony formation, migration and invasion in a dose-dependent manner, while not inhibiting CRC cell apoptosis from flow cytometry assay. Sirtuin2 (SIRT2), a member of the sirtuin protein family, plays a critical role in growth and metastasis in various cancers. Moreover, DUb inhibited CRC progression by upregulating SIRT2. These findings reveal that DUb has the potential to a novel drug for the treatment of CRC by inhibiting CRC cell proliferation.

SUBMITTER: Li J

PROVIDER: S-EPMC8844026 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Decylubiquinone Inhibits Colorectal Cancer Growth Through Upregulating Sirtuin2.

Li Jinlian J Zheng Shuting S Cheng Ting T Li Yuanyuan Y Mai Xiaobin X Jiang Guangchun G Yang Yongxia Y Zhang Qianqian Q Li Jiangchao J Zheng Lingyun L Wang Lijing L Qi Cuiling C

Frontiers in pharmacology 20220201

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Decylubiquinone (DUb), a coenzyme Q10 analog, was reported to inhibit breast cancer growth and metastasis by us. However, the influence of DUb on CRC remains unclear. Herein, we found that DUb significantly inhibited CRC growth in the patient-derived xenograft (PDX) and CT26 xenograft models. DUb was further identified to significantly suppress CRC cell proliferation, colony formation, migration and invasion ...[more]

PMID: 35177983

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Project description:BackgroundGrb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.MethodsThe expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.ResultsUp-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.ConclusionsThe results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.

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Decylubiquinone Inhibits Colorectal Cancer Growth Through Upregulating Sirtuin2.

Publications

Decylubiquinone Inhibits Colorectal Cancer Growth Through Upregulating Sirtuin2.

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