scholarly journals MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

2016 ◽  
Vol 113 (37) ◽  
pp. E5481-E5490 ◽  
Author(s):  
Sarah Anderson ◽  
Kumud Raj Poudel ◽  
Minna Roh-Johnson ◽  
Thomas Brabletz ◽  
Ming Yu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Rho Gtpase ◽  
Chemotherapeutic Agents ◽  
Full Length ◽  
Colorectal Tumors ◽  
Colon Cancer Cells ◽  
Intestinal Tumors ◽  
Invasive Front ◽  
Metastasis Model

MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration.

scholarly journals Tumor Suppressive Role of ARHGAP17 in Colon Cancer Through Wnt/β-Catenin Signaling

2018 ◽  
Vol 46 (5) ◽  
pp. 2138-2148 ◽  
Author(s):  
Shengli Pan ◽  
Yingying Deng ◽  
Jun Fu ◽  
Yuhao Zhang ◽  
Zhijin Zhang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Rho Gtpase ◽  
Gene Set Enrichment Analysis ◽  
Cell Counting ◽  
Normal Colonic Mucosa ◽  
Colon Cancer Cells

Background/Aims: A few Rho GTPase activating proteins (RhoGAPs) have been identified as tumor suppressors in a variety of human cancers. ARHGAP17, a member of RhoGAPs, has been reported to be involved in the maintenance of tight junction and epithelial barrier. The present study aimed to explore its expression in colon cancer and the possible function in colonic carcinogenesis. Methods: The mRNA and protein expression was assessed by realtime PCR and immunoblotting, respectively. Cell Counting Kit-8 (CCK-8) and Transwell assays were performed to evaluate cell proliferation and invasion, respectively. Results: We found that ARHGAP17 expression was obviously lower in colon cancer specimens than in normal colonic mucosa. ARHGAP17 expression was associated with tumor stage, size and differentiation. In vitro analysis demonstrated that ARHGAP17 overexpression inhibited cell growth and invasion of HCT-8 and HCT-116 cells. In addition, an in vivo experimental metastasis model showed that ARHGAP17 overexpression restricted cancer metastasis to the lung. Mechanically, we found that Wnt signaling contributed to the functions of ARHGAP17 in colon cancer cells. Gene set enrichment analysis (GSEA) in The Cancer Genome Atlas dataset showed that the Wnt signaling pathway was negatively associated with ARHGAP17 expression. The mRNA expression of β-catenin (an important signaling transducer of canonical Wnt signaling) gene (CTNNB1) was negatively correlated with ARHGAP17 expression. Immunoblot analysis of downstream effectors of β-catenin (c-Myc/p27 and MMP7) in ARHGAP17 overexpressing colon cancer cells and metastatic tumors within the lung also validated the GSEA result. ARHGAP17 overexpression increased the phosphorylation of glycogen synthetase kinase 3β, and decreased β-catenin nuclear localization and transcriptional activity. Furthermore, inhibition of Wnt signaling by Wnt Inhibitor Factor-1 (WIF-1) in HIEC cells with ARHGAP17 knockdown significantly attenuated the promotion effects of ARHGAP17 knockdown on cell proliferation, invasion and the activation of β-catenin. Conclusion: these results suggest that ARHGAP17 might serve as a tumor suppressor in colon cancer progression and metastasis through Wnt/β-catenin signaling pathway.

Restoration of full-length APC protein in SW480 colon cancer cells induces exosome-mediated secretion of DKK-4

2012 ◽  
Vol 33 (12) ◽  
pp. 1873-1880 ◽  
Author(s):  
Justin W. E. Lim ◽  
Rommel A. Mathias ◽  
Eugene A. Kapp ◽  
Meredith J. Layton ◽  
Maree C. Faux ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Full Length ◽  
Colon Cancer Cells ◽  
Apc Protein

scholarly journals Chemotherapeutic agents attenuate CXCL12-mediated migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Murray J. Cutler ◽  
Erica L. Lowthers ◽  
Cynthia L. Richard ◽  
Dagmar M. Hajducek ◽  
Paul A. Spagnuolo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Colon Cancer Cells

E phage gene transfection associated to chemotherapeutic agents increases apoptosis in lung and colon cancer cells

2011 ◽  
Vol 2 (3) ◽  
pp. 163-167 ◽  
Author(s):  
Ana R. Rama ◽  
Jose Prados ◽  
Consolacion Melguizo ◽  
Pablo J. Álvarez ◽  
Raúl Ortiz ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Gene Transfection ◽  
Chemotherapeutic Agents ◽  
Colon Cancer Cells ◽  
Phage Gene

scholarly journals Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells

2020 ◽  
Vol 21 (6) ◽  
pp. 2143 ◽  
Author(s):  
Annalisa Pecoraro ◽  
Pietro Carotenuto ◽  
Brunella Franco ◽  
Rossella De Cegli ◽  
Giulia Russo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Ribosome Biogenesis ◽  
Chemotherapeutic Agents ◽  
Rrna Synthesis ◽  
Autophagic Flux ◽  
Colon Cancer Cells ◽  
Nucleolar Stress ◽  
Autophagic Process

The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116p53−/− cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.

scholarly journals Regulatory role of sphingolipid metabolites, sphingosine-1-phosphate and C16:0 ceramide, in immunogenic cell death of colon cancer cells induced by Bak/Bax-activation.

2021 ◽  
Author(s):  
Jeremy A. Hengst ◽  
Asvelt J. Nduwumwami ◽  
Jong K. Yun
Keyword(s):  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Regulatory Role ◽  
Immunogenic Cell Death ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Sphingosine 1 Phosphate

We have previously identified sphingolipid metabolism as a key intracellular process associated with immunogenic cell death (ICD) induced by mitoxantrone in colon cancer cells. Specifically, we have demonstrated that inhibition of the sphingosine kinases (SphKs) synergistically enhanced production of hallmarks of ICD including ectoCRT production. To better understand the mechanism associated with ICD enhanced by SphK1-inhibition, we focused on the ER stress-associated intracellular signaling pathways leading to ectoCRT production. It is known that ABT-263 and AZD-5991 (ABT/AZD) are inhibitors of Bcl-2/Bcl-XL and MCL-1, respectively, leading to activation of Bak/Bax. Herein, we now provide evidence that treatment of DLD-1 colon cancer cells with ABT/AZD results in the production of ectoCRT indicative of ICD. Additionally, our data show that ABT/AZD-induced ectoCRT production is significantly enhanced by combination treatment with the SphK1 inhibitor, PF-543. Mechanistically, we demonstrate that combined treatment of ABT/AZD+PF-543 induces ectoCRT exposure in a caspase 8-dependent manner. Accordingly, we have identified a Bak/Bax activation-dependent pathway that leads to activation of a pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling that attenuates ectoCRT production. Additionally, we have identified a regulatory role of ceramide synthase 6 (CerS6)-C16:0 Cer in transporting of dimeric CRT to the cell surface (ectoCRT). Together, these results indicate that sphingolipid metabolites, such as S1P and C16:0 Cer, have a key regulatory role for survival/death decisions of cancer cells in response to ICD-inducing chemotherapeutic agents such as mitoxantrone and ABT/AZD. Hence, targeting SphKs may be an innovative means to enhance the efficacy of ICD-inducing chemotherapeutic agents promoting anti-tumor innate/adaptive immune response since SphK inhibition blocks the anti-ICD effects of S1P while simultaneously accumulating sphingosine (Sph) leading to pro-ICD C16:0 Cer synthesis.

Sign in / Sign up

Export Citation Format

Share Document