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Basic Research Paper

Bacillus Calmette-Guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy

Jae-Min Yuk, Dong-Min Shin, Kyoung-Sub Song, Kyu Lim, Ki-Hye Kim, Sang-Hee Lee, Jin-Man Kim, Ji-Sook Lee, Tae-Hyun Paik, Jun-Sang Kim and Eun-Kyeong Jo

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The cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guerin (BCG/CWS) is an effective anti-tumor 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.

Authors

Jae-Min Yuk

Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University; Daejeon, Korea

Dong-Min Shin

Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University; Daejeon, Korea

Kyoung-Sub Song

Department of Biochemistry; Chungnam National University; Daejeon, Korea

Kyu Lim

Departments of Biochemistry and Infection Signaling Network Research Center; Cancer Research Institute; Chungnam National University; Daejeon, Korea

Ki-Hye Kim

Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University; Daejeon, Korea

Sang-Hee Lee

Molecular Genomics Laboratory; Department of Biological Science; KAIST; Daejeon, Korea

Jin-Man Kim

Departments of Pathology and Infection Signaling Network Research Center; Cancer Research Institute; Chungnam National University; Daejeon, Korea

Ji-Sook Lee

Infection Signaling Network Research Center; Cancer Research Institute; Chungnam National University; Daejeon, Korea

Tae-Hyun Paik

Infection Signaling Network Research Center; Cancer Research Institute; Chungnam National University; Daejeon, Korea

Jun-Sang Kim Corresponding author: k423j@cnu.ac.kr

Radiation Oncology; Chungnam National University Hospital; Daejeon, Korea; Cancer Research Institute; Chungnam National University; Daejeon, Korea

Eun-Kyeong Jo Corresponding author: hayoungj@cnu.ac.kr

Department of Microbiology; Infection Signaling Network Research Center; Research Institute for Medical Sciences; College of Medicine; Chungnam National University; Daejeon, Korea

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.