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Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells.

Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial-mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.
AuthorsWei-Hsiu Liu, Ming-Teh Chen, Mong-Lien Wang, Yi-Yen Lee, Guang-Yuh Chiou, Chian-Shiu Chien, Pin-I Huang, Yi-Wei Chen, Ming-Chao Huang, Shih-Hwa Chiou, Yang-Hsin Shih, Hsin-I Ma
JournalOncotarget (Oncotarget) Vol. 6 Issue 3 Pg. 1750-68 (Jan 30 2015) ISSN: 1949-2553 [Electronic] United States
PMID25638155 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Brain Neoplasms (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Movement (physiology)
  • Cisplatin (pharmacology)
  • Drug Resistance, Neoplasm
  • Female
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Rhabdoid Tumor (drug therapy, metabolism, pathology)
  • STAT3 Transcription Factor (metabolism)
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factors (metabolism)

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