title: The HMGB1 protein sensitizes colon carcinoma cells to cell death triggered by pro-apoptotic agents.
abstract: The HMGB1 protein has multiple functions in tumor biology and can act both as a transcription factor and as a cytokine. HMGB1 is released during cell death, and in our previous studies we demonstrated that HMGB1 induces a distinct, necrosis-like cell death in glioblastoma. In epithelial malignant tumors such as colorectal cancer (CRC), the HMGB1-dependent effects show cross-talk with apoptotic signal transduction. Treatment of CRC cells with low concentrations of recombinant HMGB1 results in dose-dependent cytotoxicity which is morphologically characterized by the formation of giant mitochondria and does not share features of apoptosis. HMGB1-triggered cell death is associated with intracellular ROS release, and overexpression of Bcl-2 blocks both the increase of ROS as well as HMGB1-dependent cell death. Importantly, treatment with recombinant HMGB1 or overexpression of endogenous HMGB1 strongly sensitizes CRC cells to the cytotoxic activity of the pro-apoptotic death ligand TRAIL as well as the small molecule Bcl-2 family inhibitor ABT‑737. Moreover, treatment of CRC cells with TRAIL or ABT‑737 induces a release of endogenous HMGB1 into the extracellular space, and preincubation with glycyrrhizin, an HMGB1 inhibitor, significantly inhibits induction of cell death by TRAIL and ABT‑737, suggesting that HMGB1 functionally contributes to the execution of cell death triggered by pro-apoptotic agents. Finally, we investigated the expression of HMGB1 in human CRC tumor samples and found that loss of HMGB1 expression is associated with a more aggressive phenotype and a more advanced stage of disease in patients with CRC. Altogether, our findings demonstrate a functional link between cytotoxic signaling cascades triggered by HMGB1 and pro-apoptotic agents leading to an HMGB1-dependent sensitization to CRC cell death. Thus, a further evaluation of recombinant HMGB1 as part of an experimental combination treatment of CRC seems warranted.
authors.affiliation: Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Chengcheng Christine
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.affiliation: Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.affiliation: Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019695:Glycyrrhizic Acid / Q000008:administration & dosage; D045325:HCT116 Cells; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009596:Nitrophenols / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019695:Glycyrrhizic Acid