title: Overactivation of Ras signaling pathway in CD133+ MPNST cells.
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 β-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 IRE1α 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.
authors.affiliation: KUMC-Molecular Medicine Laboratory, Department of Medicine, The University of Kansas Medical Center, Kansas city, KS 66160, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Borrego-Diaz
authors.forename: Kaoru
authors.initials: K
authors.lastname: Terai
authors.forename: Kristina
authors.initials: K
authors.lastname: Lialyte
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Wise
authors.forename: Tuba
authors.initials: T
authors.lastname: Esfandyari
authors.forename: Fariba
authors.initials: F
authors.lastname: Behbod
authors.forename: Victor F
authors.initials: VF
authors.lastname: Mautner
authors.forename: Melanie
authors.initials: M
authors.lastname: Spyra
authors.forename: Sarah
authors.initials: S
authors.lastname: Taylor
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Faris
authors.initials: F
authors.lastname: Farassati
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D018317:Nerve Sheath Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D018631:ras Proteins