Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased extracellular pressure or shear stress activate a complex signal pathway that stimulates integrin binding affinity and potentiates metastatic cell adhesion. Inhibiting either focal adhesion kinase (FAK) and Akt1 can block this pathway, but risks interfering with the diverse other functions of each kinase. However, the mechanotransduced signal pathway involves a novel Akt1-FAK interaction not required for most FAK or Akt1 function, so modeling and blocking this interaction seems a desirable target. Building upon previous work suggesting that FAK-Akt1 binding is mediated by the FAK F1 lobe, we demonstrated that independently expressing the F1 domain in human Caco-2 or murine CT-26 colon cancer cells by transient or stable inducible plasmid expression respectively prevents the stimulation of cancer cell adhesion by increased extracellular pressure. Serial further truncation of the FAK F1 lobe identified shorter regions capable of pulling down Akt1 on a glutathione S-transferase (GST) - conjugated column. Ultimately, we identified a 33 residue segment (residues 94-126) at the C-terminal of the F1 lobe as sufficient to pull down Akt1. These findings raise the possibility of developing a treatment modality around the disruption of the FAK-Akt1 interaction using peptides modeled from FAK.
 ...
PMID:The C-terminal region of the focal adhesion kinase F1 domain binds Akt1 and inhibits pressure-induced cell adhesion. 2882 Mar 94

Mixed lineage kinase 3 (MLK3) functions in migration and/or invasion of several human cancers; however, the role of MLK3 in colorectal cancer (CRC) invasion is unknown. MLK3 is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) which activates MAPK pathways through either kinase-dependent or -independent mechanisms. Human colorectal tumors display increased levels of reactive oxygen species (ROS) or oxidative stress. ROS, such as H2O2, are important for carcinogenesis and activate MAPK signaling pathways. In human colorectal carcinoma (HCT116) cells treated with H2O2, extracellular signal-regulated kinases 1 and 2 (ERK1/2) were activated and MLK3 exhibited reduced electrophoretic mobility (shift) in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which was eliminated by phosphatase treatment. Pretreatment with the ROS scavenger N-acetyl-L-cysteine, the ERK1/2 inhibitor UO126, or ERK1/2 siRNA knockdown blocked the H2O2-induced shift of MLK3, while MLK3 inhibition with Cep1347 did not. In co-immunoprecipitation experiments performed on H2O2-treated HCT116 cells, endogenous MLK3 associated with endogenous ERK1/2 and B-Raf. Active ERK1 phosphorylated kinase dead FLAG-MLK3 in vitro, whereas ERK1 phosphorylation of kinase dead FLAG-MLK3-S705A-S758A was reduced. Both MLK3 siRNA knockdown and FLAG-MLK3-S705A-S758A expression decreased ERK1/2 activation in H2O2-treated cells. Prolonged H2O2 treatment activated ERK1/2 and promoted invasion of colon cancer cells, which was attenuated by MLK3 siRNA knockdown. Furthermore, S705A-S758A-FLAG-MLK3 demonstrated decreased oxidative-stress induced colon cancer cell invasion, but increased interaction with GST-B-Raf as compared with wild-type-FLAG-MLK3 in H2O2-treated cells. These results suggest oxidative stress stimulates an ERK1/2-dependent phosphorylation of MLK3 on Ser705 and Ser758, which promotes MLK3-dependent B-Raf and ERK1/2 activation; this positive feedback loop enhances the invasion of colon cancer cells.
 ...
PMID:MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells. 2908 9

We investigated the immunohistochemical staining characteristics of cytochrome P450 1A1 (CYP1A1), CYPB1, CYP2E1, and glutathione S-transferase P1 (GSTP1), GSTT1, GSTO1, GSTK1 in colon tumor and surrounding normal colon tissues. Tissues were obtained from 47 patients with colon adenocarcinoma and the staining intensity of tumor and control tissues was compared. CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTT1, GSTO1 and GSTK1 expressions in colon cancer cells were significantly greater than those in normal colon epithelial cells. No significant relation was found between the isoenzyme expressions and age, gender, smoking status, tumor grade and tumor stage. The higher expressions of CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTO1, GSTT1 and GSTK1 in tumor than in normal colon tissues may be important for colon cancer progression and development.
 ...
PMID:Expression of CYP and GST in human normal and colon tumor tissues. 3009 68

Colon cancer is one of the most malignant cancers. Histone modification is closely related to tumour development. Our study explored the functions of anti-silencing function 1A (ASF1A) on H4Y72ph in colon cancer cells. Colon cancer cell lines and clinical specimens were obtained and/or transfected with full length ASF1A or interference mRNA to mimic or silence of ASF1A expression. Immunoprecipitation and GST pull down was used to target targeting ASF1A or H4Y72ph. Cells were transfected with H4WT- or H4Y72F-expressing. An in vitro kinase activity assay was set to determine whether ASF1A could phosphorylate H4. The severity of autophagy was measured by detecting number of autophagosomes, number of EGFP-LC3, LC3-II/I, percentage of degradation and expression of autophagy associated gene (ATG). ASF1A positively regulated H4Y72ph; Immunoprecipitation assay and GST pull down results showed that ASF1A interacted directly with H4. In addition, ASF1A silence inhibited autophagosomes number, EGFP-LC3 number, LC3-II/I, percentage of degradation and ATG expression. Moreover, H4Y72F impaired the promoting autophagy effects of ASF1A. The ASF1A-H4Y72ph axis promoted colon cancer autophagy via transcriptional regulation of ATG genes. ASF1A regulated H4Y72ph and promotes autophagy in colon cancer cells via a kinase activity through regulation of ATG.
 ...
PMID:ASF1A regulates H4Y72 phosphorylation and promotes autophagy in colon cancer cells via a kinase activity. 3218 Apr 71

Objective: To investigate Livin-mediated regulation of H2A.XY142 phosphorylation via a novel kinase activity and its effect on autophagy in colon cancer cells. Methods: The interaction between Livin and H2A.X was tested by immunoprecipitation. H2A.X-/- HCT116 cells were transfected with human influenza hemagglutinin (HA)-tagged WT or Y142F phospho-dead mutantH2A.X plasmids. GST-tagged recombinant Livin protein was used to perform in vitro pull-down experiment and kinase assay. H2A.X-/-Livin+/+ SW480 cells were co-transfected with H2A.XWT/H2A.XY142F plasmid and LC3 EGFP-tagged plasmid to explore whether H2A.XY142F was involved in Livin-mediated autophagy induced by starvation in colon cancer cells. Results: Co-immunoprecipitation studies confirmed that Livin interacted with H2A.X and that it was phosphorylation dependent. In vitro kinase assay confirmed that Livin could phosphorylate H2A.X. Knockdown of Livin (Livin-/-) in SW480 cells or HCT116 cells canceled the starvation-induced autophagy in colon cancer cells; H2A.X-/-Livin+/+ SW480 cells transfected with H2A.XWT activated autophagy induced by starvation while cells transfected with H2A.XY142F had no significant difference; Livin-H2A.XY142F axis activated autophagy in colon cancer cells through transcriptionally regulating ATG5 and ATG7. Conclusion: Livin promotes autophagy in colon cancer cells via regulating the phosphorylation of H2A.XY142.
 ...
PMID:Livin Regulates H2A.XY142 Phosphorylation and Promotes Autophagy in Colon Cancer Cells via a Novel Kinase Activity. 3179 93

Objective To explore the influence of cyanidin-3-O-glucoside (C3G) on the proliferation of colorectal cancer cells and its mechanism. Methods In vitro binding and in vitro kinase assay were used to detect the binding ability of C3G and T-LAK cell-originated protein kinase (TOPK) and its effect on TOPK activity. Soft AGAR test was used to detect the effect of C3G on the clonal ability of colon cancer cells. The cytotoxicity of C3G was determined by MTS assay. E. coli BL21 was used to express GST-histone H3 fusion protein. The effect of C3G on the clonogenesis of colon cancer cells with silenced TOPK was examined by lentivirus infection. The phosphorylation of histone H3 by C3G in HCT116 cells was determined by Western blotting. A mouse model of xenograft was established to study the phosphorylation level of histone H3 by immunohistochemical staining. Results C3G was directly bound to TOPK in vitro and inhibited TOPK activity. C3G inhibited the proliferation and clone formation of colon cancer cells in a concentration-dependent manner. Silencing TOPK decreased the sensitivity of colon cancer cells to C3G. C3G inhibited the phosphorylation of histone H3 downstream of TOPK in a time- and concentration-dependent manner. In addition, C3G inhibited tumor growth in mice with xenograft tumors from colon cancer tissues of a patient. Conclusion C3G can inhibit colorectal cancer growth by targeting TOPK.
 ...
PMID:[Cyanidin-3-O-glucoside inhibits proliferation of colorectal cancer cells by targeting TOPK]. 3189 9

Bavachinin is a flavanone obtained from the Chinese herb, Fructus Psoraleae. Flavonoids and flavanones are recognized as cancer preventive agents. We investigated the anticancer properties of bavachinin using a model of dimethylhydrazine (DMH and dextran sodium sulfate (DSS) induced rat colon cancer. We investigated aberrant crypt foci (ACF), hyperplastic lesions, catalase (CAT), superoxide dismutase (SOD) and glutathione (GST) levels in Wistar rats. Expression of cancer biomarkers including IL-6, p53, Bcl2 and BAX was investigated. We found that bavachinin administered to rats re-established the colonic crypts that were damaged by DMH and prevented progression of the cancer.
 ...
PMID:Bavachinin mitigates DMH induced colon cancer in rats by altering p53/Bcl2/BAX signaling associated with apoptosis. 3266 69

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS (mKRAS) and BRAF (mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRAS and mBRAF cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRAS and mBRAF cells in vitro and suppressed tumorigenesis of the xenografted mKRAS tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAS colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.
 ...
PMID:A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations. 3271 31


<< Previous 1 2 3 4 5 6 7 8 9