Overactivation of Ras signaling pathway in CD133+ MPNST cells

Emma Borrego-Diaz, Kaoru Terai, Kristina Lialyte, Amanda L. Wise, Tuba Esfandyari, Fariba Behbod, Victor F. Mautner, Melanie Spyra, Sarah Taylor, Luis F. Parada, Meena Upadhyaya, Faris Farassati

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133? cells were capable of forming spheres in non-adherent/serum-free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133? cells showed enhanced invasiveness which was linked to the increased expression of b-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133? population, endoplasmic reticulum stress marker IRE1a was decreased, implying the potential sensitivity of CD133? to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133? cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133? MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133? cells supporting previous studies observing enhanced chemoresistance of these cells.

Original languageEnglish (US)
Pages (from-to)423-434
Number of pages12
JournalJournal of Neuro-Oncology
Volume108
Issue number3
DOIs
StatePublished - Jul 1 2012

Keywords

  • CD133
  • Cancer stem cells
  • Malignant peripheral nerve sheath tumor
  • Ral
  • Ras
  • Tumor-initiating cells

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Fingerprint Dive into the research topics of 'Overactivation of Ras signaling pathway in CD133+ MPNST cells'. Together they form a unique fingerprint.

  • Cite this

    Borrego-Diaz, E., Terai, K., Lialyte, K., Wise, A. L., Esfandyari, T., Behbod, F., Mautner, V. F., Spyra, M., Taylor, S., Parada, L. F., Upadhyaya, M., & Farassati, F. (2012). Overactivation of Ras signaling pathway in CD133+ MPNST cells. Journal of Neuro-Oncology, 108(3), 423-434. https://doi.org/10.1007/s11060-012-0852-1