title: Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and β-catenin signaling pathways.
abstract: Activation of signal transducer and activator of transcription 3 (STAT3) is associated with poor clinical outcome of glioblastoma (GBM). However, the role of STAT3 in resistance to alkylator-based chemotherapy remains unknown. Here, we retrospectively analyzed the phosphorylated STAT3 (p-STAT3) profile of 68 GBM patients receiving alkylator therapy, identifying p-STAT3 as an independent unfavorable prognostic factor for progression-free and overall survival. Additionally, elevated p-STAT3 expression correlated with resistance to alkylator therapy. In vitro analysis revealed that U251 and U87 human glioma cells were refractory to treatment with the common alkylating agent temozolomide (TMZ), with only a modest impact on AKT and β-catenin activation in the context of high p-STAT3. Inhibition of STAT3 in these cells significantly enhanced the effect of TMZ. Inhibition of STAT3 dramatically decreased the IC50 of TMZ, increasing TMZ-induced apoptosis while up-regulating expression of Bcl-2 and down-regulating expression of Bax. Furthermore, inhibition of STAT3 increased TMZ-induced G₀-G₁ arrest and decreased Cyclin D1 expression compared to TMZ alone. Together, these results indicate that inhibition of STAT3 sensitizes glioma cells to TMZ, at least in part, by blocking the p-AKT and β-catenin pathways. These findings strongly support the hypothesis that STAT3 inhibition significantly improves the clinical efficacy of alkylating agents.
authors: Glioma Center, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, PR China.
authors: Yongzhi
authors: Y
authors: Wang
authors: Lingchao
authors: L
authors: Chen
authors: Zhaoshi
authors: Z
authors: Bao
authors: Shouwei
authors: S
authors: Li
authors: Gan
authors: G
authors: You
authors: Wei
authors: W
authors: Yan
authors: Zhendong
authors: Z
authors: Shi
authors: Yanwei
authors: Y
authors: Liu
authors: Pei
authors: P
authors: Yang
authors: Wei
authors: W
authors: Zhang
authors: Lei
authors: L
authors: Han
authors: Chunsheng
authors: C
authors: Kang
authors: Tao
authors: T
authors: Jiang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D018572:Disease-Free Survival; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D020032:Tyrphostins / Q000494:pharmacology; D055815:Young Adult; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; C495270:CTNNB1 protein, human; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C519885:WP1066; D051176:beta Catenin; D003606:Dacarbazine; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide