Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3.
Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (< or =10 micromol/L) inhibited cell proliferation and induced apoptosis in two established cell lines (U87 and U251) and two primary cultures (PBT015 and PBT022) from human glioblastomas. The effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated signal transducers and activators of transcription 3 (STAT3; Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the effects of sorafenib, consistent with a role for STAT3 inhibition in the response to sorafenib. Phosphorylated Janus-activated kinase (JAK)1 was inhibited in U87 and U251 cells, whereas phosphorylated JAK2 was inhibited in primary cultures. Sodium vanadate, a general inhibitor of protein tyrosine phosphatases, blocked the inhibition of phosphorylation of STAT3 (Tyr705) induced by sorafenib. These data indicate that the inhibition of STAT3 activity by sorafenib involves both the inhibition of upstream kinases (JAK1 and JAK2) of STAT3 and increased phosphatase activity. Phosphorylation of AKT was also reduced by sorafenib. In contrast, mitogen-activated protein kinases were not consistently inhibited by sorafenib in these cells. Two key cyclins (D and E) and the antiapoptotic protein Mcl-1 were downregulated by sorafenib in both cell lines and primary cultures. Our data suggest that inhibition of STAT3 signaling by sorafenib contributes to growth arrest and induction of apoptosis in glioblastoma cells. These findings provide a rationale for potential treatment of malignant gliomas with sorafenib. Mol Cancer Ther; 9(4); 953-62. (c)2010 AACR.
Yang
Fan
F
Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Brown
Christine
C
Buettner
Ralf
R
Hedvat
Michael
M
Starr
Renate
R
Scuto
Anna
A
Schroeder
Anne
A
Jensen
Michael
M
Jove
Richard
R
D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D015513:Oncogene Proteins / Q000378:metabolism; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D001557:Benzenesulfonates; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D004273:DNA, Neoplasm; D015850:Interleukin-6; D050505:Mutant Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015513:Oncogene Proteins; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019938:Cyclin D1; D019000:Phosphotyrosine; D009536:Niacinamide; D014638:Vanadates; D000077157:Sorafenib; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases