The Microbiota-Derived Metabolite of Quercetin, 3,4-Dihydroxyphenylacetic Acid Prevents Malignant Transformation and Mitochondrial Dysfunction Induced by Hemin in Colon Cancer and Normal Colon Epithelia Cell Lines

Meat diet plays a pivotal role in colorectal cancer (CRC). Hemin, a metabolite of myoglobin, produced after meat intake, has been involved in CRC initiation. The compound, 3,4-dihydroxyphenylacetic acid (3,4HPAA) is a scarcely studied microbiota-derived metabolite of the flavonoid quercetin (QUE), which exert antioxidant properties. The aim of this study was to determine the protective effect of 3,4HPAA against malignant transformation (increased cell proliferation, decreased apoptosis, DNA oxidative damage and augmented reactive oxidative species (ROS) levels) and mitochondrial dysfunction induced by hemin in normal colon epithelial cells and colon cancer cells. The effect of 3,4HPAA was assessed in comparison to its precursor, QUE and to a known CRC protective agent, sulforaphane (SFN). The results showed that both, tumor and normal cells, exposed to hemin, presented increased cell proliferation, decreased caspase 3 activity and cytochrome c release, as well as augmented production of intracellular and mitochondrial ROS. In addition, hemin decreased the mitochondrial membrane potential (MMP) and the activity of complexes I and II of the electron transport chain. These effects of hemin were prevented by the action of 3,4HPAA. The metabolite showed to be more active than QUE and slightly less active than SFN. In conclusion, 3,4HPAA administration could represent a promising strategy for preventing malignant transformation and mitochondrial dysfunction in colon epithelia induced by hemin.

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Neutral endopeptidase depletion decreases colon cancer cell proliferation and TGF-β1 synthesis in indirect co-cultures with normal colon fibroblasts

Clinical & Translational Oncology ◽

10.1007/s12094-020-02537-x ◽

2021 ◽

Author(s):

M. Mizerska-Kowalska ◽

K. Sawa-Wejksza ◽

A. Sławińska-Brych ◽

M. Kandefer-Szerszeń ◽

B. Zdzisińska

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Neutral Endopeptidase ◽

Colon Cancer Cell ◽

Cancer Cell Proliferation ◽

Normal Colon ◽

Tgf Β1

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NF-κB regulates colon cancer cell proliferation and tumorigenicity

Gastroenterology ◽

10.1016/s0016-5085(01)83060-2 ◽

2001 ◽

Vol 120 (5) ◽

pp. A615-A615

Author(s):

S KUWADA ◽

C SCAIFE ◽

J KUANG ◽

R DAYNES

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Colon Cancer Cell ◽

Cancer Cell Proliferation

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Recent Advances in Understanding the effects of Obesity on Stem Cell Proliferation and the Development of Colon Cancer

10.28967/jdmms.2018.01.18001 ◽

2018 ◽

Vol 3 (1) ◽

pp. 1-9

Author(s):

Bridgette King ◽

◽

Chaodong Wu

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Stem Cell ◽

Stem Cell Proliferation ◽

Recent Advances

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Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

International Journal of Molecular Sciences ◽

10.3390/ijms22158117 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8117

Author(s):

Nunzia D’Onofrio ◽

Elisa Martino ◽

Luigi Mele ◽

Antonino Colloca ◽

Martina Maione ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Current Knowledge ◽

Apoptotic Cell ◽

Critical Role ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

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Sulforaphane induces colorectal cancer cell proliferation through Nrf2 activation in a p53-dependent manner

Applied Biological Chemistry ◽

10.1186/s13765-020-00578-y ◽

2020 ◽

Vol 63 (1) ◽

Author(s):

Yunjeong Gwon ◽

Jisun Oh ◽

Jong-Sang Kim

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Cancer Cell ◽

Related Factor ◽

Mild Stress ◽

Dependent Manner ◽

Cancer Cell Proliferation ◽

Nrf2 Signaling Pathway ◽

Dose Dependent

AbstractSulforaphane is a well-known phytochemical that stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant cellular response. In this study, we found that sulforaphane promoted cell proliferation in HCT116 human colon cancer cells expressing a normal p53 gene in a dose-dependent but biphasic manner. Since p53 has been reported to contribute to cell survival by regulating various metabolic pathways to adapt to mild stress, we further examined cellular responses in both p53-wild-type (WT) and p53-knockout (KO) HCT116 cells exposed to sulforaphane in vitro and in vivo. Results demonstrated that sulforaphane treatment activated Nrf2-mediated antioxidant enzymes in both p53-WT and p53-KO cells, decreased apoptotic protein expression in WT cells but increased in KO cells in a dose-dependent manner, and increased the expression of a mitochondrial biogenesis marker PGC1α in WT cells but decreased in KO cells. Moreover, a low dose of sulforaphane promoted tumor growth, upregulated the Nrf2 signaling pathway, and decreased apoptotic cell death in p53-WT HCT116 xenografts compared to that in p53-KO HCT116 xenografts in BALB/c nude mice. These findings suggest that sulforaphane can influence colon cancer cell proliferation and mitochondrial function through a crosstalk between the Nrf2 signaling pathway and p53 axis.

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Integrated analysis of potential pathways by which aloe-emodin induces the apoptosis of colon cancer cells

Cancer Cell International ◽

10.1186/s12935-021-01942-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dongxiao Jiang ◽

Shufei Ding ◽

Zhujun Mao ◽

Liyan You ◽

Yeping Ruan

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Caspase 3 ◽

Time Dependent ◽

Integrated Analysis ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Dapi Staining ◽

Aloe Emodin

Abstract Background Colon cancer is a malignant gastrointestinal tumour with high incidence, mortality and metastasis rates worldwide. Aloe-emodin is a monomer compound derived from hydroxyanthraquinone. Aloe-emodin produces a wide range of antitumour effects and is produced by rhubarb, aloe and other herbs. However, the mechanism by which aloe-emodin influences colon cancer is still unclear. We hope these findings will lead to the development of a new therapeutic strategy for the treatment of colon cancer in the clinic. Methods We identified the overlapping targets of aloe-emodin and colon cancer and performed protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. In addition, we selected apoptosis pathways for experimental verification with cell viability, cell proliferation, caspase-3 activity, DAPI staining, cell cycle and western blotting analyses to evaluate the apoptotic effect of aloe-emodin on colon cancer cells. Results The MTT assay and cell colony formation assay showed that aloe-emodin inhibited cell proliferation. DAPI staining confirmed that aloe-emodin induced apoptosis. Aloe-emodin upregulated the protein level of Bax and decreased the expression of Bcl-2, which activates caspase-3 and caspase-9. Furthermore, the protein expression level of cytochrome C increased in a time-dependent manner in the cytoplasm but decreased in a time-dependent manner in the mitochondria. Conclusion These results indicate that aloe-emodin may induce the apoptosis of human colon cancer cells through mitochondria-related pathways.

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The value of miR-510 in the prognosis and development of colon cancer

Open Medicine ◽

10.1515/med-2021-0251 ◽

2021 ◽

Vol 16 (1) ◽

pp. 795-804

Author(s):

Junjie Hang ◽

Feifei Wei ◽

Zhiying Yan ◽

Xianming Zhang ◽

Kequn Xu ◽

...

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cultured Cells ◽

Malignant Tumors ◽

Prognostic Indicator ◽

Tumor Promoter ◽

Migration And Invasion ◽

Clinical Prognosis ◽

Normal Tissues ◽

Novel Therapeutic Strategies

Abstract Purpose Colon cancer is one of the malignant tumors that threatens human health. miR-510 was demonstrated to play roles in the progression of various cancers; its dysregulation was speculated to be associated with the development of colon cancer. Methods One hundred and thirteen colon cancer patients participated in this research. With the help of RT-qPCR, the expression of miR-510 in collected tissues and cultured cells was analyzed. The association between miR-510 expression level and clinical features and prognosis of patients was evaluated. Moreover, the effects of miR-510 on cell proliferation, migration, and invasion of colon cancer were assessed by CCK8 and Transwell assay. Results miR-510 significantly upregulated in colon cancer tissues and cell lines relative to the adjacent normal tissues and colonic cells. The expression of miR-510 was significantly associated with the TNM stage and poor prognosis of patients, indicating miR-510 was involved in the disease progression and clinical prognosis of colon cancer. Additionally, the upregulation of miR-510 significantly promoted cell proliferation, migration, and invasion of colon cancer, while its knockdown significantly inhibited these cellular processes. SRCIN 1 was the direct target of miR-510 during its promoted effect on the development of colon cancer. Conclusion The upregulation of miR-510 acts as an independent prognostic indicator and a tumor promoter by targeting SRCIN 1 in colon cancer, which provides novel therapeutic strategies for colon cancer.

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