Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The poor response to drug therapy often seen in hepatocellular carcinoma requires insight into the molecular interplay responsible for intrinsic or acquired drug resistance. We previously demonstrated that the CD133-/EpCAM- subpopulation of the Huh-7 hepatoma cell line features aberrant activation of the hedgehog signaling (Hh) pathway and chemoresistance. The prevailing hypothesis of the present study is that hedgehog signaling may govern expression of ATP-binding cassette (ABC) transporters, which are responsible for drug resistance in the CD133-/EpCAM- subpopulation. Our aim is to reveal the molecular interplay in the mediation of drug resistance with a newly established Huh-7 subpopulation featuring high Hh signaling activity and drug resistance. In this study, chemoresistance was determined in a newly established Huh-7-DN subpopulation featuring the CD133-/EpCAM- surface marker profile, aberrant expression of Hh pathway, and epithelial-mesenchymal transition (EMT). Expression of ABC transporter proteins (ABCB1, ABCC1, and ABCG2) and Hh transcription factor Gli-1/2 was evaluated with and without Hh signaling antagonists LDE225 or itraconazole. We found that hedgehog signaling activity as determined by transfection with a Gli-Lux reporter cassette and gene expression levels tended to increase from Huh-7 CD133+/EpCAM+ to CD133-/EpCAM-, and the highest levels were found in Huh-7-DN cells. The Huh-7-DN subpopulation exhibited characteristics of EMT as evidenced by increased expression of vimentin and loss of E-cadherin. Sorafenib significantly inhibited the viability of all subpopulations except the Huh-7-DN subpopulation. Compared with other sorafenib-sensitive subpopulations, the Huh-7-DN subpopulation showed enhanced expression of Hh transcription factor Gli-2 and ABCC1 transporter protein. Silencing Gli-2 by lentivirus harboring shRNA against Gli-2 or LDE225 significantly suppressed expression of Gli-2 and ABCC1 genes in Huh-7-DN subpopulation. In conclusion, aberrant hedgehog signaling activation is linked to poor differentiation, epithelial-mesenchymal transition, and chemoresistance in the Huh-7-DN subpopulation. Hedgehog signaling transcription factor Gli-2 appears to be the primary regulator for drug sensitivity of hepatoma through the ABCC1 transporter.
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PMID:Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter. 2841 25

Background and Aim: Hairy enhancer of split-1 (HES1) is a downstream transcriptional factor of Notch signaling pathway, which was found to be related to chemoresistance. This study was aimed to investigate the role of HES1 in chemoresistance of colorectal cancer (CRC). Methods: Tissue microarray was used to analyze the clinical significance of HES1 in radical resected (R0) stage II/III CRC patients that received adjuvant chemotherapy. 5-fluorouracil (5-Fu) chemoresistance was examined in CRC cell lines (RKO and HCT8, LOVO) with stable over-expression and inhibition of HES1 gene by cytotoxicity test. Gene expression microarray was used to investigate the enriched pathways and different expressed of genes in cells with over-expressed HES1. Expression changes of the chemoresistance related genes were confirmed by qPCR and western blot analysis. Results: Stage II CRC patients with higher HES1 expression showed higher recurrence rate after chemotherapy. Colon cancer cell lines which over-expressed HES1 were more resistant to 5-Fu treatment in vitro. Gene expression microarray revealed that HES1 was related to the signaling pathways of epithelial-mesenchymal transition (EMT) and drug metabolism. Immunofluorescence assay showed HES1 over-expression lead to depressed E-cadherin and elevated N-cadherin. QPCR and western blot analysis confirmed that ABCC1, ABCC2 and P-gp1 were induced after HES1 over-expression. Conclusions: HES1 promotes chemoresistance to 5-Fu by prompting EMT and inducing of several ABC transporter genes. HES1 might be a novel therapeutic target in CRC treatment.
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PMID:HES1 Promotes Colorectal Cancer Cell Resistance To 5-Fu by Inducing Of EMT and ABC Transporter Proteins. 2892 69