Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy

Abstract

The cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guerin (BCG/CWs) is an effective antitumor immunotherapy agent. here, we demonstrate that BCG/CWs has a radiosensitizing effect on colon cancer cells through the induction of autophagic cell death. exposure of HCT116 colon cancer cells to BCG/CWs before ionizing radiation (IR) resulted in increased cell death in a caspase-independent manner. Treatment with BCG/CWs plus IR resulted in the induction of autophagy in colon cancer cells. either the autophagy inhibitor 3-methyladenine or knockdown of beclin 1 or Atg7 significantly reduced tumor cell death induced by BCG/CWs plus IR, whereas the caspase inhibitor z-VAD-fmk failed to do so. BCG/CWs plus IR-mediated autophagy and cell death was mediated predominantly by the generation of reactive oxygen species (ROS). The c-Jun NH2-terminal kinase pathway functioned upstream of ROS generation in the induction of autophagy and cell death in HCT116 cells after co-treatment with BCG/CWs and IR. Furthermore, toll-like receptor (TLR) 2, and in part, TLR4, were responsible for BCG/CWs-induced radiosensitization. In vivo studies revealed that BCG/ CWs-mediated radiosensitization of HCT116 xenograft growth is accompanied predominantly by autophagy. Our data suggest that BCG/CWs in combination with IR is a promising therapeutic strategy for enhancing radiation therapy in colon cancer cells through the induction of autophagy. © 2010 Landes Bioscience.