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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Chen, Hsiao-Yun^1,6  Lin, Liang-Ting^2,4,6  Wang, Mong-Lien^2,3,6  Tsai, Kun-Ling^5,6  Huang, Pin-I^1,3,7  Yang, Yi-Ping^1,7,11  Lee, Yi-Yen⁸  Chen, Yi-Wei^1,3,7  Lo, Wen-Liang^1,9  Lan, Yuan-Tzu^1,3,6  Chiou, Shih-Hwa^1,2,3,6  Lin, Chien-Min^10,12  Ma, Hsin-I^13,14  Chen, Ming-Teh^3,8 

[1] Natl Yang Ming Univ, Inst Clin Med, Taipei, Taiwan

[2] Natl Yang Ming Univ, Inst Pharmacol, Taipei, Taiwan

[3] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan

[4] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China

[5] Natl Cheng Kung Univ, Dept Phys Therapy, Tainan, Taiwan

[6] Taipei Vet Gen Hosp, Dept Med Res, Taipei, Taiwan

[7] Taipei Vet Gen Hosp, Ctr Canc, Taipei, Taiwan

[8] Taipei Vet Gen Hosp, Neurol Inst, Dept Neurosurg, Taipei, Taiwan

[9] Taipei Vet Gen Hosp, Dept Stomatol, Div Oral & Maxillofacial Surg, Taipei, Taiwan

[10] Taipei Med Univ, Coll Med, Sch Med, Dept Surg, Taipei, Taiwan

[11] Triserv Gen Hosp, Natl Def Med Ctr, Dept Neurosurg, Taipei, Taiwan

[12] Taipei Med Univ, Shuang Ho Hosp, Dept Neurosurg, Taipei, Taiwan

[13] Triserv Gen Hosp, Dept Neurol Surg, Taipei, Taiwan

[14] Natl Def Med Ctr, Taipei, Taiwan

关键词: Glioblastoma multiforme;    Musashi-1;    PKR;    Stress granule;    Drug resistance;   

DOI  :  10.1016/j.bbadis.2018.02.017

来源: Elsevier

【 摘 要 】

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 eIF2 alpha 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/eIF2 alpha 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 eIF2 alpha, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2 alpha 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/eIF2 alpha signalling cascade.

【 授权许可】

Free