PuSH - Publication Server of Helmholtz Zentrum München: Proapoptotic and antiapoptotic proteins of the Bcl-2 family regulate sensitivity of pancreatic cancer cells toward gemcitabine and T-cell-mediated cytotoxicity.

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Bauer, C.* ; Hees, C.* ; Sterzik, A.* ; Bauernfeind, F.* ; Mak'Anyengo, R.* ; Duewell, P.* ; Lehr, H.A.* ; Nößner, E. ; Wank, R.* ; Trauzold, A.* ; Endres, S.* ; Dauer, M.* ; Schnurr, M.*

Proapoptotic and antiapoptotic proteins of the Bcl-2 family regulate sensitivity of pancreatic cancer cells toward gemcitabine and T-cell-mediated cytotoxicity.

J. Immunother. 38, 116-126 (2015)

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Open Access Green as soon as Postprint is submitted to ZB.

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Sensitivity of carcinoma cells towards gemcitabine (Gem) has been linked to mitochondrial apoptotic proteins. Recently, we described synergistic efficacy of Gem-based chemoimmunotherapy and a dendritic cell (DC) tumor vaccine in a murine pancreatic carcinoma model. Here, we investigated the role of the mitochondrial proteins Bcl-2, Bcl-xL, and Bax for sensitization of pancreatic carcinoma cells toward T-cell-mediated cytotoxicity alone and in combination with Gem. Bcl-2 expression was silenced by siRNA in Panc02 pancreatic cancer cells expressing the model antigen ovalbumin (PancOVA). Tumor cells were treated with Gem and/or siRNA, and cytotoxicity induced by OVA-specific cytotoxic T lymphocytes (CTL) from OT-1 mice was assessed. Gem-induced and T-cell-induced cytotoxicity was also studied in human Colo357 pancreatic cancer cell lines overexpressing Bax or Bcl-xL. Apoptosis induction by Fas-activating antibody was measured by Annexin V staining. The in vivo capacity of Bcl-2 siRNA to augment CTL efficacy induced by DC vaccinations was assessed in C57BL/6 mice bearing PancOVA tumors. PancOVA cells treated with Bcl-2 siRNA were sensitized towards both Gem and T-cell-mediated killing; combination therapy exhibited an additive effect. Bax overexpression sensitized Colo357 cells to both Gem-mediated and T-cell-mediated cytotoxicity, whereas Bcl-xL overexpression was inhibitory. Combining Bcl-2 silencing with DC therapy improved tumor control in the PancOVA model in vivo without affecting the number of tumor-reactive CTL. In conclusion, expression of Bcl-2, Bcl-xL, and Bax in pancreatic tumor cells determines sensitivity towards both Gem-mediated and CTL-mediated toxicity. Bcl-2 silencing could be exploited therapeutically in tumor vaccine approaches.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Bcl-2 ; Chemotherapy ; Dendritic Cells ; Gemcitabine ; Mitochondrial Proteins ; Pancreatic Carcinoma ; Sirna ; Vaccination; Pulsed Dendritic Cells; Granzyme-b; Adenocarcinoma Cells; Prostate Carcinoma; Positive Selection; Caspase Activation; Signaling Pathway; Induced Apoptosis; Human-melanoma; Solid Tumors

ISSN (print) / ISBN 1524-9557

e-ISSN 1537-4513

Journal Journal of Immunotherapy

Quellenangaben Volume: 38, Issue: 3, Pages: 116-126

Publisher Lippincott Williams & Wilkins

Publishing Place Philadelphia

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Immunology (IMI)