Intrinsic metabolic as well as extrinsic therapeutic stress during conventional cancer treatment induces cancer cells to overexpress Damage-Associated Molecular Pattern molecules (DAMPs). Their increased release into necrotic or injured regions within the tumor microenvironment regulates cell death (e.g. apoptosis) and cell survival (e.g. autophagy) in both adjacent and distant (systemic) tissues. The prototypic DAMP, High Mobility Group Box 1 (HMGB1), is a highly conserved nuclear protein with multiple intracellular and extracellular functions, including transcriptional regulation and modulation of inflammation and immunity. We recently demonstrated that HMGB1 is an essential regulator of autophagy, a cellular catabolic process that facilitates the degradation of cytoplasmic components using the lysosomal machinery. Based on our findings, we hypothesize that our central hypothesis is that HMGB1 overexpression and release in response to cancer therapy activates autophagy thereby increasing resistance to therapy and promoting tumor growth. To test this hypothesis, genetic, biochemical and cell biological studies will be utilized to characterize whether and how HMGB1 increases resistance of pancreatic cancer cells to chemotherapeutic agents such as gemcitabine through autophagic regulation. The experimental approach to specifically target HMGB1 will utilize novel HMGB1 pancreatic conditional knockout mice that we have created, HMGB1 neutralizing antibodies, and HMGB1 specific shRNA. The long term goal of this project is to improve the outcome of patients receiving cancer therapies by developing a novel strategy to target pancreatic cancer, a disease associated with low survival rates as well as a high degree of intrinsic and/or acquired resistance to therapy. These studies will provide new insights into HMGB1 signaling and the role of autophagy in tumor therapy. This deeper understanding will be used to improve the effectiveness of existing pancreatic cancer therapies.

Public Health Relevance

During the past several years, it has become increasingly clear that the understudied cellular process of autophagy is an important regulator of cancer development and response to treatment. Increasing evidence suggests that autophagy is an important resistance mechanism in established cancers in response to chemotherapy, radiation therapy, and immunotherapy. The focus of the proposed study is to investigate the molecular basis of sustained autophagy in the setting of tumor treatment with a specific focus on a novel pro- autophagic protein, HMGB1, which contributes to the efficacy of various anti-cancer agents and provides a rationale for the manipulation of autophagy during cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160417-03
Application #
8685752
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2012-09-10
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$308,787
Indirect Cost
$107,512
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Huang, Jin; Xie, Yangchun; Sun, Xiaofang et al. (2015) DAMPs, ageing, and cancer: The 'DAMP Hypothesis'. Ageing Res Rev 24:16-Mar
Liu, Ke; Huang, Jun; Xie, Min et al. (2014) MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell. Autophagy 10:442-52
Sun, Xiaofang; Tang, Daolin (2014) HMGB1-dependent and -independent autophagy. Autophagy 10:1873-6
Song, X; Kim, S-Y; Zhang, L et al. (2014) Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer. Cell Death Dis 5:e1504
Chen, R; Kang, R; Fan, X-G et al. (2014) Release and activity of histone in diseases. Cell Death Dis 5:e1370
Liu, Liying; Yang, Minghua; Kang, Rui et al. (2014) HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation through RAGE. Biochem Biophys Res Commun 450:851-6
Yang, Liangchun; Xie, Min; Yang, Minghua et al. (2014) PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 5:4436
Tang, Daolin; Kang, Rui; Van Houten, Bennett et al. (2014) High mobility group box 1 (HMGB1) phenotypic role revealed with stress. Mol Med 20:359-62
Kang, Rui; Zhang, Qiuhong; Hou, Wen et al. (2014) Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology 146:1097-107
Kang, R; Tang, D; Schapiro, N E et al. (2014) The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene 33:567-77

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