Autophagy has recently attracted increasing attention for its role in conferring resistance to various commonly used anticancer
therapies. Whereas its activities are known primarily to be under regulation of the high mobility group box-1 (
HMGB1) gene, the expression of
HMGB1 and its function in
leukemia cells still remain unclear. In this study, we found that
HMGB1 was expressed abundantly in various kinds of both
leukemia and non-
blood cancer cell-lines, and its expression was positively correlated with clinical status in childhood
leukemia. In
leukemia cells, when endogenous
HMGB1 increased
starvation-induced autophagy, this reaction was inhibited by the suppression of
HMGB1. While the use of autophagy inhibitor,
3-methyladenine (3-MA), blocked the autophagic reaction and increased
leukemia cell sensitivity to
chemotherapy, enhancing
HMGB1 expression decreased this sensitivity. Notably, suppressing
HMGB1 expression also increased
leukemia cell chemosensitivity. Furthermore, the
phosphatidylinositol 3-kinase (PI3K)/Akt/
mammalian target of rapamycin complex 1 (
mTORC1) pathway was found to be functionally connected with
HMGB1.
HMGB1 gene transfection increased the LC3-II level and inhibited phosphorylation of Akt and
p70S6K levels. Knockdown of
HMGB1 expression blocked the association between mTOR and raptor in the setting of enhanced autophagy. When class I PI3K was inhibited by PI3K-I
shRNA, it decreased the PI3K-I expression level. Knockdown of
HMGB1 expression had no further effects on LC3-II. These results suggest that endogenous
HMGB1 is an intrinsic regulator of autophagy in
leukemia cells and it enhances
leukemia cell chemoresistance likely through the PI3K/Akt/
mTORC1 pathway.