The role of the high mobility group box 1 (
HMGB1) protein in
chemotherapy-induced cell death was examined. CT26 mouse
colon cancer cells were treated with
trichostatin A (
TSA; apoptosis inducer) or
doxorubicin (DXR;
necrosis inducer). DXR increased
HMGB1 concentration in CT26 cell culture medium, whereas
TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or
TSA was injected in a single tumour. After injection, serum
HMGB1 concentration in DXR-treated mice was 10 times higher than that in
TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with
TSA. In mouse models, lung and liver
metastasis was enhanced by DXR but not by
TSA. DXR-enhanced
metastasis was abrogated by anti-HMGB1 antibody treatment. In a
cancer dormancy model, DXR induced regrowth of quiescent CT26 cells.
HMGB1 induced tumour
necrosis factor-α secretion via
Toll-like receptor (TLR)4 in U937 monocytes; however,
HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via
receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on
nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that
HMGB1 released from necrotic
cancer cells treated with a
necrosis inducer enhances regrowth and
metastasis of remnant
cancer cells via RAGE activation.