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
Kang, Rui; Zhu, Shan; Zeh, Herbert et al. (2018) The STING-STAT6 pathway drives Cas9-induced host response in human monocytes. Biochem Biophys Res Commun 506:278-283
Liao, Yuning; Xia, Xiaohong; Liu, Ningning et al. (2018) Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination. Oncogene 37:1896-1910
Li, Changfeng; Zhang, Ying; Cheng, Xing et al. (2018) PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Dev Cell 46:441-455.e8
Deng, Wenjun; Zhu, Shan; Zeng, Ling et al. (2018) The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. Cell Rep 24:366-378
Kang, Rui; Kroemer, Guido; Tang, Daolin (2018) The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med :
Kang, Rui; Zeng, Ling; Zhu, Shan et al. (2018) Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe 24:97-108.e4
Chen, Ruochan; Zhu, Shan; Fan, Xue-Gong et al. (2018) High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis. Hepatology 67:1823-1841
Song, Xinxin; Zhu, Shan; Chen, Pan et al. (2018) AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc- Activity. Curr Biol 28:2388-2399.e5
Wang, Ding; Xie, Nan; Gao, Wanli et al. (2018) The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 503:1689-1695
Song, Xinxin; Zhu, Shan; Xie, Yangchun et al. (2018) JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology 154:1480-1493

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