Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma.
Glioblastoma multiform (GBM) is one of the most lethal human malignant brain tumors with high risks of recurrence and poor treatment outcomes. The RNA-binding protein Musashi-1 (MSI1) is a marker of neural stem/progenitor cells. Recent study showed that high expression level of MSI1 positively correlates with advanced grade of GBM, where MSI1 increases the growth of GBM. Herein, we explore the roles of MSI1 as well as the underlying mechanisms in the regulation of drug resistance and tumorigenesis of GBM cells. Our results demonstrated that overexpression of MSI1 effectively protected GBM cells from drug-induced apoptosis through down-regulating pro-apoptotic genes; whereas inhibition of AKT withdrew the MSI1-induced anti-apoptosis and cell survival. We further showed that MSI1 robustly promoted the secretion of the pro-inflammatory cytokine IL-6, which was governed by AKT activity. Autonomously, the secreted IL-6 enhanced AKT activity in an autocrine/paracrine manner, forming a positive feedback regulatory loop with the MSI1-AKT pathway. Our results conclusively demonstrated a novel drug resistance mechanism in GBM cells that MSI1 inhibits drug-induced apoptosis through AKT/IL6 regulatory circuit. MSI1 regulates both cellular signaling and tumor-microenvironmental cytokine secretion to create an intra- and intercellular niche for GBM to survive from chemo-drug attack.
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Hsiao-Yun
HY
Chen
Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Liang-Ting
LT
Lin
Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Mong-Lien
ML
Wang
Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Shu-Hsien
SH
Lee
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Ming-Long
ML
Tsai
Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
Chi-Chang
CC
Tsai
Graduate Institute of Medical Sciences, National Defense Medical Center, Department of Neurological Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Wei-Hsiu
WH
Liu
Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Tzu-Chien
TC
Chen
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Graduate Institute of Medical Sciences, National Defense Medical Center, Department of Neurological Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Yi-Ping
YP
Yang
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Yi-Yen
YY
Lee
Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Yuh-Lih
YL
Chang
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
Pin-I
PI
Huang
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
Yi-Wei
YW
Chen
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
Wen-Liang
WL
Lo
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Shih-Hwa
SH
Chiou
Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Ming-Teh
MT
Chen
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction
C508600:IL6 protein, human; D015850:Interleukin-6; C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
GBM; IL-6; Musashi-1; apoptosis; chemoresistance