Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma

Hsiao Yun Chen, Liang Ting Lin, Mong Lien Wang, Kun Ling Tsai, Pin I. Huang, Yi Ping Yang, Yi Yen Lee, Yi Wei Chen, Wen Liang Lo, Yuan Tzu Lan, Shih Hwa Chiou, Chien Min Lin, Hsin I. Ma, Ming Teh Chen

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Abstract

Musashi-1 (MSI1), one of the RNA-binding proteins, is abundantly found not only in neural stem cells but also in several cancer tissues and has been reported to act as a positive regulator of cancer progression. Growing evidence indicates that PKR and eIF2α play pivotal roles in the stimulation of stress granule formation as well as in the subsequent translation modulation in response to stressful conditions; however, little is known about whether MSI1 is involved in this PKR/eIF2α cancer stem cell-enhancing machinery. In this study, we demonstrated that MSI1 promotes human glioblastoma multiforme (GBM) stem cells and enhances chemoresistance when exposed to sublethal stress. The overexpression of MSI1 leads to a protective effect in mitigating drug-induced cell death, thus facilitating the formation of chemoresistant stress granules (SGs) in response to arsenic trioxide (ATO) treatment. SG components, such as PKR and eIF2α, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2α contribute to the downstream enhancement of stem cell genes, thereby promoting the progression of GBM. The silencing of MSI1 or PKR both obviously withdrew the phenomena. Taken together, our findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2α signalling cascade.

Original languageEnglish
Pages (from-to)1850-1861
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number5
DOIs
Publication statusPublished - 2018 May

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

Chen, H. Y., Lin, L. T., Wang, M. L., Tsai, K. L., Huang, P. I., Yang, Y. P., Lee, Y. Y., Chen, Y. W., Lo, W. L., Lan, Y. T., Chiou, S. H., Lin, C. M., Ma, H. I., & Chen, M. T. (2018). Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(5), 1850-1861. https://doi.org/10.1016/j.bbadis.2018.02.017