Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy.
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 NH(2)-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.
Yuk
Jae-Min
JM
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea.
Shin
Dong-Min
DM
Song
Kyoung-Sub
KS
Lim
Kyu
K
Kim
Ki-Hye
KH
Lee
Sang-Hee
SH
Kim
Jin-Man
JM
Lee
Ji-Sook
JS
Paik
Tae-Hyun
TH
Kim
Jun-Sang
JS
Jo
Eun-Kyeong
EK
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002277:Carcinoma / Q000473:pathology / Q000532:radiotherapy*; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D017358:Cell Wall Skeleton / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000502:physiology / Q000648:ultrastructure*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017358:Cell Wall Skeleton; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D020169:Caspases