title: Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway.
abstract: BACKGROUND
  There is increasing evidence supporting the concept of cancer stem cells (CSCs), which are responsible for the initiation, growth and metastasis of tumors. CSCs are thus considered the target for future cancer therapies. To achieve this goal, identifying potential therapeutic targets for CSCs is essential.
  
  
  METHODS
  We used a natural product of vitamin E, gamma tocotrienol (gamma-T3), to treat mammospheres and spheres from colon and cervical cancers. Western blotting and real-time RT-PCR were employed to identify the gene and protein targets of gamma-T3 in mammospheres.
  
  
  RESULTS
  We found that mammosphere growth was inhibited in a dose dependent manner, with total inhibition at high doses. Gamma-T3 also inhibited sphere growth in two other human epithelial cancers, colon and cervix. Our results suggested that both Src homology 2 domain-containing phosphatase 1 (SHP1) and 2 (SHP2) were affected by gamma-T3 which was accompanied by a decrease in K- and H-Ras gene expression and phosphorylated ERK protein levels in a dose dependent way. In contrast, expression of self-renewal genes TGF-beta and LIF, as well as ESR signal pathways were not affected by the treatment. These results suggest that gamma-T3 specifically targets SHP2 and the RAS/ERK signaling pathway.
  
  
  CONCLUSIONS
  SHP1 and SHP2 are potential therapeutic targets for breast CSCs and gamma-T3 is a promising natural drug for future breast cancer therapy.
authors: Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, The corner of Cooper Rd. St Lucia, Brisbane, QLD 4072, Australia. w.gu@uq.edu.au.
authors: Wenyi
authors: W
authors: Gu
authors: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. i.prasadam@qut.edu.au.
authors: Indira
authors: I
authors: Prasadam
authors: Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, The corner of Cooper Rd. St Lucia, Brisbane, QLD 4072, Australia. m.yu2@uq.edu.au.
authors: Meihua
authors: M
authors: Yu
authors: School of Biomedical Science, the University of Queensland, Brisbane, Australia. fengxia.zhang@uqconnect.edu.au.
authors: Fengxia
authors: F
authors: Zhang
authors: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. mingtat.ling@qut.edu.au.
authors: Patrick
authors: P
authors: Ling
authors: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. yin.xiao@qut.edu.au.
authors: Yin
authors: Y
authors: Xiao
authors: Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, The corner of Cooper Rd. St Lucia, Brisbane, QLD 4072, Australia. c.yu@uq.eud.au.
authors: Chengzhong
authors: C
authors: Yu
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D018874:Spheroids, Cellular / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002839:Chromans; D014810:Vitamin E; C013649:plastochromanol 8; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018631:ras Proteins