scholarly journals The Relationship between TP53 Gene Status and Carboxylesterase 2 Expression in Human Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Momoko Ishimine ◽  
Hyeon-Cheol Lee ◽  
Hirofumi Nakaoka ◽  
Hajime Orita ◽  
Toshiyuki Kobayashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Evidence ◽  
Tp53 Gene ◽  
Mrna Levels ◽  
Missense Mutations ◽  
Human Colorectal Cancer ◽  
Mutational Status ◽  
Colorectal Cancer Cells ◽  
Gene Status ◽  
The Relationship

Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1.5-fold lower) than the adjacent normal tissue, and only 30% (12 of 37) showed similar (<1.5-fold lower) or higher CES2 mRNA levels. However, TP53 gene sequencing revealed no relationship between CES2 downregulation and TP53 mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1MET, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with TP53 missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53.

scholarly journals Inhibitory effect of selenomethionine on carcinogenesis in the model of human colorectal cancer in vitro and its link to the Wnt/β-catenin pathway.

2018 ◽  
Vol 65 (3) ◽  
Author(s):  
Edyta Korbut ◽  
Agata Ptak-Belowska ◽  
Tomasz Brzozowski
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Colorectal Carcinogenesis ◽  
Mrna Levels ◽  
Human Colorectal Cancer ◽  
Bax Protein ◽  
Colorectal Cancer Cells ◽  
Gsk 3Β ◽  
Ht 29

Selenium compounds have been implicated as anticancer agents; however, the mechanism of their inhibitory action against cancer development has not been extensively investigated. The constitutive activation of the Wnt/β-catenin pathway is a central event in colorectal carcinogenesis. In this pathway, the excessive cell proliferation is initiated by the generation of β-catenin followed by overexpression of proto-oncogenes such as c-Myc. It is believed that under physiological conditions the level of c-Myc is efficiently controlled by accessibility of β-catenin protein through the process of phosphorylation by glycogen synthase kinase 3β (GSK-3β). Here, we determined whether selenomethionine (SeMet) can inhibit cell growth and affect the Wnt/β-catenin pathway in HT-29 human colorectal cancer cells in vitro. The effective cytotoxic doses of SeMet have been selected after 48 h of incubation of this compound with colorectal cancer HT-29 cell line. The MTT assay was used to assess cell viability and the protein and mRNA levels of β-catenin and c-Myc were determined by Western blotting and qPCR, respectively. The SeMet potently inhibited growth of HT-29 cells, significantly decreased the β-catenin protein and mRNA concentration, down-regulated the c-Myc gene expression and up-regulated pro-apoptotic Bax protein expression. Moreover, SeMet increased the level of GSK-3β phosphorylated at serine 9 (S9) and significantly increased the level of β-catenin phosphorylated at S33 and S37. We conclude that SeMet suppresses the growth of HT-29 colorectal cancer cells by the mechanism linked to the Wnt/β-catenin pathway, however, the degradation of β-catenin may occur independently of GSK-3β catalytic activity and its phosphorylation status.

Vitex rotundifolia Fruit Suppresses the Proliferation of Human Colorectal Cancer Cells through Down-regulation of Cyclin D1 and CDK4 via Proteasomal-Dependent Degradation and Transcriptional Inhibition

2018 ◽  
Vol 46 (01) ◽  
pp. 191-207 ◽  
Author(s):  
Hun Min Song ◽  
Gwang Hun Park ◽  
Su Bin Park ◽  
Hyun-Seok Kim ◽  
Ho-Jun Son ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcriptional Regulation ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Mrna Levels ◽  
Human Colorectal Cancer ◽  
Gastrointestinal Infections ◽  
Down Regulation ◽  
Colorectal Cancer Cells

Viticis Fructus (VF) as the dried fruit from Vitex rotundifolia L. used as a traditional medicine for treating inflammation, headache, migraine, chronic bronchitis, eye pain, and gastrointestinal infections has been reported to have antiproliferative effects against various cancer cells, including breast, lung and colorectal cancer cells. However, the molecular mechanisms by which VF mediates the inhibitory effect of the proliferation of cancer cells have not been elucidated in detail. In this study, we investigated the molecular mechanism of VF on the down-regulation of cyclin D1 and CDK4 level associated with cancer cell proliferation. VF suppressed the proliferation of human colorectal cancer cell lines such as HCT116 and SW480. VF induced decrease in cyclin D1 and CDK4 in both protein and mRNA levels. However, the protein levels of cyclin D1 and CDK4 were decreased by VF at an earlier time than the change of mRNA levels; rather it suppressed the expression of cyclin D1 and CDK4 via the proteasomal degradation. In cyclin D1 and CDK4 degradation, we found that Thr286 phosphorylation of cyclin D1 plays a pivotal role in VF-mediated cyclin D1 degradation. Subsequent experiments with several kinase inhibitors suggest that VF-mediated degradation of cyclin D1 may be dependent on GSK3[Formula: see text] and VF-mediated degradation of CDK4 is dependent on ERK1/2, p38 and GSK3[Formula: see text]. In the transcriptional regulation of cyclin D1 and CDK4, we found that VF inhibited Wnt activation associated with cyclin D1 transcriptional regulation through TCF4 down-regulation. In addition, VF treatment down-regulated c-myc expression associated CDK4 transcriptional regulation. Our results suggest that VF has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.

scholarly journals Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 982
Author(s):  
Motoki Watanabe ◽  
Yasumasa Yamada ◽  
Yoichi Kurumida ◽  
Tomoshi Kameda ◽  
Mamiko Sukeno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thymidylate Synthase ◽  
Magnetic Beads ◽  
Adenine Nucleotide ◽  
Mrna Levels ◽  
Lead Compound ◽  
Human Colorectal Cancer ◽  
Mitochondrial Inner Membrane ◽  
Colorectal Cancer Cells ◽  
Human Colorectal Cancer Cells

Natural products have numerous bioactivities and are expected to be a resource for potent drugs. However, their direct targets in cells often remain unclear. We found that rabdosianone I, which is a bitter diterpene from an oriental herb for longevity, Isodon japonicus Hara, markedly inhibited the growth of human colorectal cancer cells by downregulating the expression of thymidylate synthase (TS). Next, using rabdosianone I-immobilized nano-magnetic beads, we identified two mitochondrial inner membrane proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as direct targets of rabdosianone I. Consistent with the action of rabdosianone I, the depletion of ANT2 or PHB2 reduced TS expression in a different manner. The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor.

scholarly journals Pro-Inflammatory Microenvironment Modulates the Transfer of Mutated TP53 Mediated by Tumor Exosomes

2021 ◽  
Vol 22 (12) ◽  
pp. 6258
Author(s):  
Rossana Domenis ◽  
Adriana Cifù ◽  
Catia Mio ◽  
Martina Fabris ◽  
Francesco Curcio
Keyword(s):  
Cancer Progression ◽  
Rare Event ◽  
Tp53 Gene ◽  
Mrna Levels ◽  
Inflammatory Microenvironment ◽  
Hepatic Cells ◽  
Mutational Status ◽  
Sw480 Cells ◽  
Tumor Exosomes ◽  
The Impact

Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression.

scholarly journals Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in hct116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1856
Author(s):  
Yong-Hwi Kang ◽  
Jin-Seok Lee ◽  
Nam-Hun Lee ◽  
Seung-Hyung Kim ◽  
Chang-Seob Seo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thymidylate Synthase ◽  
Cell Cycle Distribution ◽  
Human Colorectal Cancer ◽  
Common Cancer ◽  
G1 Phase Arrest ◽  
Colorectal Cancer Cells ◽  
Coptidis Rhizoma ◽  
Underlying Mechanisms ◽  
Human Colorectal Cancer Cells

Colorectal cancer (CRC) is a malignancy of the colon or rectum. It is ranked as the third most common cancer in both men and women worldwide. Early resection permitted by early detection is the best treatment, and chemotherapy is another main treatment, particularly for patients with advanced CRC. A well-known thymidylate synthase (TS) inhibitor, 5-fluorouracil (5-FU), is frequently prescribed to CRC patients; however, drug resistance is a critical limitation of its clinical application. Based on the hypothesis that Coptidis Rhizoma extract (CRE) can abolish this 5-FU resistance, we explored the efficacy and underlying mechanisms of CRE in 5-FU-resistant (HCT116/R) and parental HCT116 (HCT116/WT) cells. Compared to treatment with 5-FU alone, combination treatment with CRE and 5-FU drastically reduced the viability of HCT116/R cells. The cell cycle distribution assay showed significant induction of the G0/G1 phase arrest by co-treatment with CRE and 5-FU. In addition, the combination of CRE and 5-FU notably suppressed the activity of TS, which was overexpressed in HCT116/R cells, as compared to HCT116/WT cells. Our findings support the potential of CRE as an adjuvant agent against 5-FU-resistant colorectal cancers and indicate that the underlying mechanisms might involve inhibition of TS expression.

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