@article{52ee2b62e7504b5c8f1e4875db655bef,
title = "Direct molecular interactions between HMGB1 and TP53 in colorectal cancer",
abstract = "Tumorigenesis and the efficacy of cancer therapeutics are both defined by the balance between autophagy and apoptosis. High-mobility group box 1 (HMGB1) is a DNA chaperone and extracellular damage-associated molecular pattern molecule (DAMP) with pro-autophagic activity. TP53/p53 plays a transcription-dependent and -independent role in the regulation of apoptosis, autophagy, metabolism, cell cycle progression, and many other processes. Both HMGB1 and TP53 are tightly linked with the development of cancer, associated with many of the hallmarks defining the altered biology of cancer. We have demonstrated that TP53-HMGB1 complexes regulate the balance between apoptosis and autophagy through regulation of the cytosolic localization of the reciprocal binding partner, whereby increased cytosolic HMGB1 enhances autophagy and increased cytosolic TP53 enhances apoptosis in colon cancer cells. We found that HMGB1-mediated autophagy promotes cell survival in TP53-dependent processes, and that TP53 inhibits autophagy through negative regulation of HMGB1-BECN1 complexes. Nuclear localization of TP53 and HMGB1 in tumors from patients with colon adenocarcinoma had a positive trend with survival time from diagnosis. Thus, HMGB1 and TP53 are critical in the crossregulation of apoptosis and autophagy and central to colon cancer biology.",
keywords = "Apoptosis, Autophagy, Colorectal cancer, HMGB1, TP53",
author = "Livesey, {Kristen M.} and Rui Kang and Zeh, {Herbert J.} and Lotze, {Michael T.} and Daolin Tang",
note = "Funding Information: {\textcopyright} 2012 Landes Bioscience. LC3 puncta, and decreased levels of HMGB1-Mediated Autophagy paired t-test, p = 0.023) than normal SQSTM1 under basal conditions relative Promotes Cell Survival colon. Linear regression was used to to TP53+/+ cells, with a further increase in determine whether HMGB1 or TP53 autophagy in response to starvation. Autophagy has been identified as a double-expression was associated with survival. TP532/2 cells and cancer cell lines with edged sword, which both promotes and There was a statistically significant asso-endogenous mutant TP53Do not(DLD-1and inhibitscelldeathddurinisgTP53-detrpendenibt uciationtwitheTP53.expressionandtimeof HT-29) have increased cytosolic apoptosis. To determine the role of survival following the first recurrence (p , HMGB1. Knockdown or pharmacological HMGB1 in TP53-dependent apoptosis 0.00761) by automated and manual inhibition of HMGB1 with ethyl pyruvate we knocked down HMGB1 in HCT116 scoring. Nuclear TP53 expression (p = in TP532/2 cells attenuates TP53 knock-cells, which restores and increases sensi-0.059, manual scoring) and nuclear out-induced autophagy. We found that tivity of TP532/2 and TP53+/+ cells, HMGB1 expression (p = 0.068, auto-cytosolic HMGB1 promotes autophagy respectively, to adriamycin-and etopo-mated scoring) demonstrate positive trends through increased complex formation with side-induced apoptosis as evaluated by with survival time from diagnosis that are BECN1. flow cytometry and a clonogenic survival not statistically significant. Thus, the Conversely, starvation of HCT116 assay. We demonstrated that this increased subcellular localization of HMGB1 and HMGB1 KD cells decreases levels of sensitivity to these DNA damaging agents TP53 are likely related to their roles in autophagy as demonstrated by decreased is mediated by decreased levels of auto-regulating survival and further studies are LC3-II expression and LC3 puncta phagy as evaluated by LC3 puncta with necessary to characterize this relationship. and increased SQSTM1 expression. HMGB1 knockdown. Autophagy inhibi- HMGB12/2cells have increased levels of tors 3-methyladenine and wortmannin cytosolic TP53 and decreased levels of also increase adriamycin-and etoposide-This project was funded by a grant from TP53 in the nucleus relative to HMGB1+/+ induced apoptosis in TP532/2 cells. the NIH 1 P01 CA 101944-04 (M.T.L.) cells, with a further accentuation in Knockdown of HMGB1 in TP532/2 cells and funding provided by the Department these differences following starvation. We also promotes BAX translocation, down-of Surgery, University of Pittsburgh (D.T. found that TP53 is not required for stream in the TP53 apoptosis pathway, and M.T.L.).",
year = "2012",
month = may,
doi = "10.4161/auto.19891",
language = "English (US)",
volume = "8",
pages = "846--848",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "5",
}