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Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells.

Signal transducers and activators of transcription 3 (STAT3) is constitutively active in human pancreatic cancer cells and can promote cell growth and apoptosis resistance that contribute to tumorigenesis. We determined if sorafenib, a multikinase inhibitor, can induce apoptosis by targeting STAT3 signaling to enhance apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Human pancreatic cancer cell lines (PANC-1 and BxPC-3) were preincubated with sorafenib (Nexavar) alone or followed by TRAIL. Apoptosis was determined by Annexin V labeling, caspase cleavage, and Bax/Bak activation. Protein expression was analyzed by immunoblotting. Knockdown of STAT3, Mcl-1, and Bim were achieved by lentiviral small hairpin RNA. Adenoviral dominant-negative or retroviral constitutively active (CA) STAT3 were also used. Sorafenib inhibited constitutive STAT3 phosphorylation (Tyr(705)) and suppressed Mcl-1 and Bcl-x(L) proteins in a dose- and time-dependent manner. CA-STAT3 overexpression was shown to attenuate caspase-3 cleavage and suppression of Mcl-1 by sorafenib. STAT3 knockdown or a DN STAT3 was shown to downregulate Mcl-1 and Bcl-x(L) and to sensitize cells to TRAIL-mediated apoptosis. Treatment with sorafenib enhanced TRAIL-induced Annexin V staining and release of mitochondrial cytochrome c and AIF. Because the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis, Bim knockdown was shown to attenuate caspase-3, caspase-9 cleavage, and Bax/Bak activation by sorafenib plus TRAIL. The suppression of STAT3 by genetic means or using sorafenib was shown to downregulate Mcl-1 and Bcl-x(L) and to sensitize cells to TRAIL-mediated apoptosis. These data indicate that targeting STAT3 may enhance treatment efficacy against pancreatic cancer.

Pubmed ID: 20197401

Authors

  • Huang S
  • Sinicrope FA

Journal

Molecular cancer therapeutics

Publication Data

March 11, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: K05 CA142885
  • Agency: NCI NIH HHS, Id: P50 CA10270
  • Agency: NCI NIH HHS, Id: P50 CA102701
  • Agency: NCI NIH HHS, Id: P50 CA102701-07

Mesh Terms

  • Antineoplastic Agents
  • Apoptosis
  • Benzenesulfonates
  • Carcinoma
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Niacinamide
  • Pancreatic Neoplasms
  • Phenylurea Compounds
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • bcl-X Protein