The Studies Of High Mobility Group Protein1(HMGB1) Increases ERK And JNK Pathways In Regulation Of Autophagy Using K562Cells

High-mobility group box1protein (HMGB1), one of the best characterized damage-associated molecular pattern (DAMP) molecule, is a chromatin associated nuclear protein. Intranuclearly, HMGB1functions as an architectural chromatin-binding factor and promotes assembly of the proteins including p53, p73, Rel/NF-κB and estrogen receptor on specific DNA targets. Extracellularly, HMGB1through interacting with the receptors RAGE and TLRs contributes to several biological functions including inflammation, cell migration, cell differentiation and tumor metastasis. Current studies reveal that HMGB1plays an important and central role in cancer. The up-regulation of HMGB1mRNA expression was found in tumors. Therefore, targeting the HMGB1ligand or its receptor represents an important potential application in cancer therapeutics.Autophagy occurs at low basal levels in all cells and is postulated to play a housekeeping role. It is part of the normal catabolic process needed for homeostasis, which is in the quality control of cellular components by recycling long-lived proteins and dysfunctional organelles, and also keeps cell prolonged survival by providing substrates under metabolic stresses. Autophagy occurs in response to disordered micro environment stimuli for H2O2, rapamycin, ER stress, mitochondrial toxins, hypoxia, abnormal cell growth, and nutrient deprivation. It is associated with multiple disease states, involving neurodegenerative disease, infection, heart disease, autophagic cell death, and cancer. Overwhelming investigations have suggested autophagy is an important resistance mechanism to chemotherapy in hematological malignancies.Studies have demonstrated that the serum levels of HMGB1are significantly high in childhood lymphocytic leukemia. Later data confirms HMGB1is a direct activator of autophagy in leukemia cells through activating PI3KC3-MEK-ERK pathway, and autophagy is a potential mechanism for HMGB1-mediated chemotherapy resistance. However, the correlation between autophagy and HMGB1in human myeloid leukemia cells remains unclear.In this paper, our results suggested that HMGB1over-expression rendered myeloid leukemia cells (K562cells) resistant to conventional anticancer treatments through increasing autophagy rather than decreaseing apoptosis. While suppression of HMGB1expression increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1over-expression resulted in an increase in the formation of autophagosome and autophagolysosome fusion, in mRNA levels of Beclin-1, VSP34and UVRAG which are key genes involved in mammalian autophagy, and in protein levels of p-Bcl-2and LC3Ⅱ. The luciferase activity assays revealed that over-expression of HMGB1increased the synergistic transcriptional activities of ERK and JNK, respectively, and the inhibition of HMGB1down-regulated the transcriptional activities of ERK and JNK. The role of HMGB1in transcriptional regulation of ERK and JNK required for autophagy provides a potential drug target for therapeutic interventions in myeloid leukemia.