Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2010, PMID: 20880848

Activation of AMP-activated protein kinase by temozolomide contributes to apoptosis in glioblastoma cells via p53 activation and mTORC1 inhibition.

Zhang, Wen-bin; Wang, Zhuo; Shu, Fei; Jin, Yong-hua; Liu, Hong-yi; Wang, Qiu-juan; Yang, Yong

Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumors including malignant glioblastoma. The mechanism of TMZ-induced glioblastoma cell death and apoptosis, however, is not fully understood. Here, we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found that methylating agents TMZ and N-methyl-N'-nitro-N-nitrosoguanidine induce AMPK activation in primary cultured human glioblastoma and glioblastoma cell lines. TMZ-induced O(6)-methylguanine production is involved in AMPK activation. O(6)-benzylguanine, an O(6)-methylguanine-DNA methyltransferase inhibitor, enhances TMZ-induced O(6)-methylguanine production, leading to enhanced reactive oxygen species production, which serves as an upstream signal for AMPK activation. Activation of AMPK is involved in TMZ-induced glioblastoma cell death and apoptosis. AMPK inhibitor (Compound C) or AMPKα siRNA knockdown inhibits TMZ-induced glioblastoma cell death and apoptosis, whereas AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside enhances it. In further studies, we found that activation of AMPK is involved in TMZ-induced p53 activation and subsequent p21, Noxa, and Bax up-regulation. Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ-induced pro-cell apoptosis effects. Our study suggests that activation of AMPK by TMZ contributes to glioblastoma cell apoptosis, probably by promoting p53 activation and inhibiting mTORC1 signaling.

Diseases/Pathways annotated by Medline MESH: Glioblastoma
Document information provided by NCBI PubMed

Text Mining Data

p53 ⊣ mTORC1: " Activation of AMP activated protein kinase by temozolomide contributes to apoptosis in glioblastoma cells via p53 activation and mTORC1 inhibition "

p53 → AMPK: " In further studies, we found that activation of AMPK is involved in TMZ induced p53 activation and subsequent p21, Noxa, and Bax up-regulation "

p21 → AMPK: " In further studies, we found that activation of AMPK is involved in TMZ induced p53 activation and subsequent p21 , Noxa, and Bax up-regulation "

Bax → AMPK: " In further studies, we found that activation of AMPK is involved in TMZ induced p53 activation and subsequent p21, Noxa, and Bax up-regulation "

mTOR complex 1 (mTORC1) ⊣ AMPK: " Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ induced pro-cell apoptosis effects "

p53 ⊣ mTORC1: " Our study suggests that activation of AMPK by TMZ contributes to glioblastoma cell apoptosis, probably by promoting p53 activation and inhibiting mTORC1 signaling "

Manually curated Databases

No curated data.