Involvement of PKCα activation in TF/VIIa/PAR2-induced proliferation, migration, and survival of colon cancer cell SW620

Wu, Biao; Zhou, Hong; Hu, Lichao; Yuan, Ming; Wu, Ying

doi:10.1007/s13277-012-0614-x

Cited by 42 publications

(48 citation statements)

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“…It has been reported that PKCα could inhibit the occurrence of intestinal cancer and the expression level of PKCα in colorectal cancer cells is low relative to other cancers [33,34]. In contrast, some studies have shown that PKCα activation can promote cancer cell proliferation, migration, survival, and drug resistance [35][36][37]. In colorectal cancer, the PKCα inhibitor can reduce cell viability and inhibit cell migration [38].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Gong

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mutations in the Ras/Raf/MEK/ERK pathway are detected in 50% of colorectal cancer cases and play a crucial role in cancer development and progression. Cobimetinib is a MEK inhibitor approved for the treatment of advanced melanoma and inhibits the cell viability of other types of cancer cells. Methods: HCT116 colorectal cancer cells were treated with cobimetinib, and MTT assay, colony formation assay, and flow cytometry were used to evaluate cell viability, cell cycle, and apoptosis, respectively. The expression of genes associated with the cell cycle and apoptosis were evaluated by quantitative real-time PCR and western blotting. To explore use of cobimetinib in colorectal cancer treatment and further understand its mechanisms, RNA-seq technology was used to identify differentially expressed genes (DEGs) between cobimetinib-treated and untreated HCT116 cells. Furthermore, we compared these DEGs with Gene Expression Omnibus data from colorectal cancer tissues and normal colonic epithelial tissues. Results: We found that cobimetinib not only inhibited cell proliferation but also induced G1 phase arrest and apoptosis in HCT116 colorectal cancer cells, suggesting that cobimetinib may useful in colorectal cancer therapy. After cobimetinib treatment, 3,495 DEGs were obtained, including 2,089 upregulated genes and 1,406 downregulated genes, and most of these DEGs were enriched in the cell cycle, DNA replication, and DNA damage repair pathways. Our results revealed that some genes with high expression in colorectal cancer tissues were downregulated by cobimetinib in HCT116 cells, including CCND1, E2F1, CDC25C, CCNE2, MYC, and PCNA. These genes have vital roles in DNA replication and the cell cycle. Furthermore, genes with low expression in colorectal cancer tissues were upregulated by cobimetinib, including PRKCA, PI3K, RTK, and PKC. Based on our results, the PKC and PI3K pathways were activated after cobimetinib treatment, and inhibition of these two pathways can increase the cytotoxicity of cobimetinib in HCT116 cells. Notably, cobimetinib appeared to enhance the efficacy of 5-fluorouracil (5-FU) by decreasing TYMS expression, high expression of which is responsible for 5-FU resistance in colorectal cancer. Conclusions: Our results suggest the potential use of cobimetinib in colorectal cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Gong

Zhu

et al. 2018

Cell Physiol Biochem

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“…Suppression of cell growth in colon cancer cells by PKC is thought to occur through the regulation of EGFR signaling [110]; ERKmediated inhibition of the inhibitor of DNA binding 1, a proproliferative factor [112]; downregulation of -catenin and its target genes cyclin D1 and c-Myc [111,113]; and PKCmediated phosphorylation of retinoic acid-related orphan nuclear receptor , which downregulates the Wnt/ -catenin signaling [114]. In contrast to these results, a recent study has suggested that PKC activation is involved in the activation of ERK1/2/NF-B through the tissue factor/VIIa/PAR2 pathway and this signaling pathway leads to enhanced proliferation, migration, and survival for the colon cancer cell line SW620 [115].…”

Section: Colonmentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes and Cancer

Kang

2014

New Journal of Science

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Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

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“…149 Other PAR2 activators like kallikrein 14 (KLK14) induced cell signaling in colon cancer cells by activating PAR2, leading to proliferative responses. 150 There are also reports suggesting that TF/FVIIa induced PAR2 activation, leading to proliferation and migration of SW620 colon cancer cells, 151,152 as well as inducing signaling, migration, and invasion of breast cancer cells. 86,153 In addition, PAR2-induced β-arrestin signaling has been shown to mediate migration of breast cancer cells, 154,155 although it is likely that other pathways are important in migration.…”

Section: ■ Par2 Functional Phenotypementioning

confidence: 99%

“…Other non-polar and polar/charged groups, including serine mimetics and nonaromatic heterocycles, in derivatives of GB88 (147)(148)(149)(150)(151)(152) were either inactive or displayed less antagonist activity than GB88. This suggested that aromaticity may be important for potency.…”

Section: Gb88mentioning

confidence: 99%

“…The pentapeptide WPLPR was derived from Oryzatensin and showed some C3aR activating activity in ileum contraction assay. [152][153] This peptide possessed guinea pig ileum-contracting activity, anti-analgesia and anti-amnesia properties when administered orally at 300 mg/kg. 153 Leu-75 was substituted with alanine, valine, isoleucine, methionine and phenylalanine but all showed dramatic loss of activity, which implied that leucine was the optimal residue at this position.…”

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confidence: 99%

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Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

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About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

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Involvement of PKCα activation in TF/VIIa/PAR2-induced proliferation, migration, and survival of colon cancer cell SW620

Cited by 42 publications

References 45 publications

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Protein Kinase C (PKC) Isozymes and Cancer

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

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