title: Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells.
abstract: BACKGROUND
  CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved.
  
  
  METHODS
  In the present study, we isolated CD133(+) cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133(-) cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133(+) cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133(+/-) cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133(+) cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB-derived CD133(+) cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133(+)-inoculated mice.
  
  
  RESULTS
  These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133(+) cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors.
authors.affiliation: Department of Pharmacy Practice, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Charn-Jung
authors.initials: CJ
authors.lastname: Chang
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chiang
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Song
authors.forename: Shen-Kou
authors.initials: SK
authors.lastname: Tsai
authors.forename: Lin-Chung
authors.initials: LC
authors.lastname: Woung
authors.forename: Chin-Hong
authors.initials: CH
authors.lastname: Chang
authors.forename: Shaw-Yeu
authors.initials: SY
authors.lastname: Jeng
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Tsai
authors.forename: Chuan-Chih
authors.initials: CC
authors.lastname: Hsu
authors.forename: Hung-Fu
authors.initials: HF
authors.lastname: Lee
authors.forename: Chi-Shuan
authors.initials: CS
authors.lastname: Huang
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Yung
authors.forename: Jorn-Hon
authors.initials: JH
authors.lastname: Liu
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D019295:Computational Biology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D014466:Ultraviolet Rays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C038106:cucurbitacin I