PMID- 37953603
OWN - NLM
STAT- MEDLINE
DCOM- 20231201
LR  - 20231217
IS  - 1521-0758 (Electronic)
IS  - 0191-3123 (Linking)
VI  - 47
IP  - 6
DP  - 2023 Nov 2
TI  - The Sonic hedgehog pathway inhibitor GDC0449 induces autophagic death in human 
      Medulloblastoma Daoy cells.
PG  - 529-539
LID - 10.1080/01913123.2023.2270676 [doi]
AB  - Medulloblastoma (MB) is a frequently occurring malignant brain tumor in children, 
      and many of these tumors are identified by the abnormal activation of the Sonic 
      Hedgehog (SHH) pathway. Although the Shh inhibitor GDC0449 initially shows some 
      effectiveness in certain tumors, they eventually recur due to drug resistance 
      mechanisms, highlighting the need for new treatment options. In this study, we 
      explore whether GDC0449 induces autophagy in the human MB cell lines. To 
      investigate the ultrastructural pathology changes of GDC0449-treated Daoy and 
      D283 cells, we employed Transmission Electron Microscopy (TEM) technology to 
      identify the expression of autophagic vacuoles. Our results indicate that GDC0449 
      only increases autophagy in Daoy cells by increasing the LC3-II/LC3-I ratio and 
      autophagosome formation.We also analyzed Beclin1, LC3, Bax, and Cleaved-caspase3 
      protein and mRNA expression levels of autophagic and apoptotic markers using 
      fluorescence confocal microscopy, RT-PCR, and Western blot. We found that cell 
      autophagy and apoptosis increased in a dose-dependent manner with GDC0449 
      treatment. Additionally, we observed increased mammalian target of rapamycin 
      (mTOR) phosphorylation and decreased protein kinase B (AKT/PKB), Ribosomal 
      Protein S6, eIF4E-binding protein (4EBP1) phosphorylation in GDC0449-treated Daoy 
      cells. It was observed that inhibiting autophagy using Beclin1 siRNA 
      significantly blocked the apoptosis-inducing effects of GDC0449, suggesting that 
      GDC0449 mediates its apoptotic effects by inducing autophagy.Our data suggests 
      that GDC0449 inhibits the growth of human MB Daoy cells by autophagy-mediated 
      apoptosis. The mechanism of GDC0449-induced autophagy in Daoy cells may be 
      related to the inhibition of the PI3K/AKT/mTOR signaling pathway.
FAU - Zhang, Qi
AU  - Zhang Q
AD  - Ultrastructural Pathology, Beijing Neurosurgical Institute, Beijing, China.
FAU - Zou, Wanjing
AU  - Zou W
AD  - Neuropathology, Beijing Neurosurgical Institute, Beijing, China.
FAU - He, Longtao
AU  - He L
AD  - Ultrastructural Pathology, Beijing Neurosurgical Institute, Beijing, China.
FAU - Zhang, Cuiping
AU  - Zhang C
AD  - Ultrastructural Pathology, Beijing Neurosurgical Institute, Beijing, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - Neural Reconstructional Department, Beijing Neurosurgical Institute, Capital 
      Medical University, Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20231130
PL  - England
TA  - Ultrastruct Pathol
JT  - Ultrastructural pathology
JID - 8002867
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (HhAntag691)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Beclin-1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Child
MH  - Humans
MH  - Proto-Oncogene Proteins c-akt/metabolism/pharmacology
MH  - Hedgehog Proteins/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism/pharmacology
MH  - Beclin-1/pharmacology
MH  - *Medulloblastoma/drug therapy
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism/pharmacology
MH  - Apoptosis
MH  - Autophagy
MH  - *Cerebellar Neoplasms/drug therapy
MH  - Cell Line, Tumor
OTO - NOTNLM
OT  - Apoptosis
OT  - GDC0449
OT  - MB
OT  - PI3K/Akt/mTOR
OT  - autophagy
EDAT- 2023/11/13 06:43
MHDA- 2023/12/01 06:44
CRDT- 2023/11/13 03:39
PHST- 2023/12/01 06:44 [medline]
PHST- 2023/11/13 06:43 [pubmed]
PHST- 2023/11/13 03:39 [entrez]
AID - 10.1080/01913123.2023.2270676 [doi]
PST - ppublish
SO  - Ultrastruct Pathol. 2023 Nov 2;47(6):529-539. doi: 10.1080/01913123.2023.2270676. 
      Epub 2023 Nov 30.