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Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer.
Pal, Deeksha; Tyagi, Ashish; Chandrasekaran, Balaji; Alattasi, Houda; Ankem, Murali K; Sharma, Arun K; Damodaran, Chendil.
Afiliación
  • Pal D; Department of Urology, University of Louisville, Louisville, KY, USA.
  • Tyagi A; Department of Urology, University of Louisville, Louisville, KY, USA.
  • Chandrasekaran B; Department of Urology, University of Louisville, Louisville, KY, USA.
  • Alattasi H; Department of Pathology, University of Louisville, Louisville, KY, USA.
  • Ankem MK; Department of Urology, University of Louisville, Louisville, KY, USA.
  • Sharma AK; Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, 17033, USA.
  • Damodaran C; Department of Urology, University of Louisville, Louisville, KY, USA. chendil.damodaran@louisville.edu.
Cell Death Dis ; 9(8): 798, 2018 07 23.
Article en En | MEDLINE | ID: mdl-30038258
ABSTRACT
Epithelial to mesenchymal transition (EMT) in colorectal cancer (CRC) has been attributed to activation of AKT and Notch1 signaling pathways. As EMT corresponds to increased aggressiveness of CRC, approaches that prevent metastasis by targeting AKT/Notch1 pathways are at the forefront of current research paradigms. This study examined the anti-metastatic potential of Verrucarin J (VJ), a small molecule, in CRC cells overexpressing AKT and Notch1. VJ significantly inhibited AKT/HCT 116 cell growth by acting on the AKT/NFκB/Bcl-2 signaling axis and initiated apoptotic signaling as was evident from increased expression of pro-apoptotic markers such as cleaved PARP, cleaved caspase 3, and cleaved caspase 9. Also, VJ inhibited the cell growth in AKT/Notch1-overexpressing CRC cells and abrogated EMT. The down-regulation of AKT and Notch1 signaling was apparent in immunoblot analysis and corresponded with down-regulation of mesenchymal markers including Snail, and ß-catenin. Intraperitoneal administration of VJ in control (pCMV/HCT 116) and AKT/HCT 116 mice significantly suppressed AKT-induced tumor growth in a xenograft model. In addition, down-regulation of prosurvival markers as well as AKT and Notch1 was observed in the immunohistochemical analysis of the xenografted tumors. In conclusion, our study substantiates the role of AKT and Notch1 in cell proliferation, angiogenesis, and EMT of CRC cells and demonstrates that VJ may be a viable therapeutic option to counter AKT-induced cell proliferation and tumor outgrowth in CRC.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Proteínas Proto-Oncogénicas c-akt / Receptor Notch1 / Transición Epitelial-Mesenquimal Límite: Animals / Humans Idioma: En Revista: Cell Death Dis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Proteínas Proto-Oncogénicas c-akt / Receptor Notch1 / Transición Epitelial-Mesenquimal Límite: Animals / Humans Idioma: En Revista: Cell Death Dis Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos