Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

Zou, Yuhui; Wang, Qiong; Li, Bingling; Xie, Bing; Wang, Weimin

doi:10.3892/mmr.2014.2151

Cited by 66 publications

(53 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Autophagy is an alternative program of cell death that may be initiated to overcome the resistance of gliomas to apoptosis. Indeed, TMZ has been reported to exert cytotoxicity by induction of autophagy in malignant glioma cells [27,40]. Our data reveal that like TMZ, analogs 1 and 2 induced autophagy in U87MG cells.…”

Section: Discussionsupporting

confidence: 52%

N3-Substituted Temozolomide Analogs Overcome Methylguanine-DNA Methyltransferase and Mismatch Repair Precipitating Apoptotic and Autophagic Cancer Cell Death

et al. 2014

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) treatment includes temozolomide (TMZ) chemotherapy. O6-Methylguanine lesions are repaired by methylguanine-DNA methyltransferase (MGMT). Response to TMZ requires low MGMT and functional mismatch repair (MMR); resistance, conferred by MGMT or MMR deficiency, represents a barrier to successful treatment. TMZ analogs were synthesized, substituting N3-methyl with propargyl (1) or sulfoxide (2). MTT assays were conducted in SNB19 and U373 isogenic glioma cell lines (V = vector control; M = MGMT-transfected). TMZ potency was reduced >5-fold in SNB19M and U373M cells; in contrast, MGMT-expressing cells were equisensitive as vector controls to analogs 1 and 2. GI₅₀ values <50 VM of analogs 1 or 2 were detected in V cells possessing acquired TMZ resistance: SNB19VR (hMSH6 loss) and U373VR (MGMT upregulation). Analogs 1 and 2 inhibited MMR-deficient colorectal carcinoma cell growth (irrespective of p53); G2/M cell cycle arrest preceded apoptosis. GH2AX foci inferred the generation of DNA double-strand breaks by analogs 1 and 2. Acridine orange-stained vesicles, intracellular punctate GFP-LC3 protein and double-membraned autophagosomes indicate that TMZ, 1 and 2 induce autophagy in apoptotis-resistant GBM cells. Analogs 1 and 2 elicit in vitro antitumor activity irrespective of MGMT, MMR and p53. Such imidazotetrazines may treat MGMT+ GBM and possess broader spectrum activity causing apoptosis and autophagy in malignancies which evade apoptosis. i 2014 S. Karger AG, Basel

show abstract

Section: Discussionsupporting

confidence: 52%

N3-Substituted Temozolomide Analogs Overcome Methylguanine-DNA Methyltransferase and Mismatch Repair Precipitating Apoptotic and Autophagic Cancer Cell Death

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[30][31][32] Accumulating evidence has unveiled the complex crosstalk between DDR pathways and autophagy. Activation of ATM [33][34][35][36] by various insults induces autophagy, and TP53 [37][38][39] and MTOR 35,36,[39][40][41] are 2 representative downstream signaling nodes connecting the DDR pathways to autophagy. The descriptions of autophagy regulation by ATR are rather scarce, but there is strong evidence showing that ATR is a potential upstream regulator of autophagy.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

View full text Add to dashboard Cite

Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

show abstract

“…TMZ induces autophagy in other ways (25). Zou et al (26) identified that TMZ inhibited the growth of glioma cells and decreased the number of cells in S and G 2 /M, leading to atypical cell apoptosis. The present study identified that the use of TMZ alone to treat U251 cells induces a slight increase in autophagy-related proteins and may induce the apoptosis of glioma cells to a certain extent, which is consistent with a previous study (15).…”

Section: Discussionmentioning

confidence: 99%

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Zhou

et al. 2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. Glioma is a malignant tumor of the glial tissue that is difficult to excise through surgery, with poor patient prognosis. The use of chemotherapeutic drugs alone to treat glioma following surgery results in a high probability of sequelae, such as tumor recurrence. The present study investigated the effects of a novel treatment combination on glioma cells and determined the molecular mechanisms underlying its action. The effect of temozolomide (TMZ) combined with rapamycin (RAPA) on the TMZ-induced autophagic death of U251 glioma cells was examined. The U251 cell line was treated with TMZ combined with RAPA, and the cell survival rate and half maximal inhibitory concentration (IC 50 ) of TMZ/RAPA was detected using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was used to detect changes in cell cycle distribution. The formation of acidic vesicular organelles (AVOs) in the cytoplasm was identified using fluorescence microscopy and quantitatively analyzed. Western blotting was performed to detect the expression levels of autophagy-associated proteins Beclin-1 and microtubule associated protein 1 light chain 3 alpha (MAP1LC3A)-I and II. RAPA (1.25 nM) combined with 5 µM TMZ markedly inhibited U251 cell growth. RAPA reinforced TMZ-induced autophagic death, reducing the IC 50 value of treatment when combined (TMZ alone, 22.5±3.23 µM vs. TMZ and RAPA, 10.35±2.81 µM). Compared with the control group, the proportion of cells in G 2 /M were markedly increased following treatment with TMZ combined with RAPA. Acridine orange staining demonstrated that TMZ combined with RAPA could markedly enhance the generation of intracellular AVOs compared with TMZ or RAPA alone. In addition, Beclin-1 and LC3-II protein expression was markedly increased compared with the control and single treatment groups (P<0.05). The results of the present study indicate that RAPA reinforces TMZ-induced autophagic death of U251 glioma cells, providing a novel therapeutic combination for the treatment of malignant glioma.

show abstract

Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

Cited by 66 publications

References 21 publications

N3-Substituted Temozolomide Analogs Overcome Methylguanine-DNA Methyltransferase and Mismatch Repair Precipitating Apoptotic and Autophagic Cancer Cell Death

N3-Substituted Temozolomide Analogs Overcome Methylguanine-DNA Methyltransferase and Mismatch Repair Precipitating Apoptotic and Autophagic Cancer Cell Death

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Contact Info

Product

Resources

About