ABSTRACT
The multiple tyrosine kinase inhibitor sorafenib has recently demonstrated clinical effects in patients with androgen-independent prostate cancer. These observations provided the rational for investigating the anti-tumoral properties of this compound on prostate cancer cell lines at the molecular level. Two hormone refractory (PC3 and DU145) and one hormone responsive cell line (22Rv1) were used. By use of a panel of cell biology techniques such as immunoblotting, flow cytometry and immunocytochemistry, effects on the MAPK pathway and induction of apoptosis and autophagy were evaluated. We demonstrate that sorafenib reduced cell viability in a dose-dependent manner, induced apoptosis and inactivated the MAPK pathway. Moreover, we show for the first time, that sorafenib treatment of prostate cancer cells also induces cellular autophagy. This feature is in accordance with the anticancer potential of sorafenib and adds another important effector mechanism of this compound. These observations may open potentially interesting treatment combinations that may augment the effect of sorafenib, either by drugs that promote autophagy such as the rapalogues, or by combining sorafenib with compounds that specifically inhibit the autophagic process.
Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Benzenesulfonates/pharmacology , Carcinoma/pathology , Prostatic Neoplasms/pathology , Pyridines/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Carcinoma/genetics , Carcinoma/metabolism , Drug Evaluation, Preclinical , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic/physiology , Genes, bcl-2/physiology , Humans , Male , Niacinamide/analogs & derivatives , Phagosomes/drug effects , Phagosomes/metabolism , Phenylurea Compounds , Phosphorylation/drug effects , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Sorafenib , Transfection , Tumor Cells, CulturedABSTRACT
Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.
