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 #
5R01CA160417-04
Application #
8890798
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2012-09-10
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kang, Rui; Xie, Yangchun; Zhang, Qiuhong et al. (2017) Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res 27:916-932
Li, Shaling; Huang, Yan; Huang, Yun et al. (2017) The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation. J Exp Clin Cancer Res 36:51
Zeng, Ling; Kang, Rui; Zhu, Shan et al. (2017) ALK is a therapeutic target for lethal sepsis. Sci Transl Med 9:
Zhu, Shan; Zhang, Qiuhong; Sun, Xiaofan et al. (2017) HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res 77:2064-2077
Xie, Yangchun; Zhu, Shan; Zhong, Meizuo et al. (2017) Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma. Gastroenterology 153:1429-1443.e5
Song, Xinxin; Zhu, Shan; Xie, Yangchun et al. (2017) JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology :
Kang, Rui; Tang, Daolin (2017) Autophagy and Ferroptosis - What's the Connection? Curr Pathobiol Rep 5:153-159
Chen, Xin; Yang, Qianqian; Xiao, Lu et al. (2017) Metal-based proteasomal deubiquitinase inhibitors as potential anticancer agents. Cancer Metastasis Rev 36:655-668
Chen, Ruochan; Zhu, Shan; Fan, Xue-Gong et al. (2017) HMGB1 Controls Liver Cancer Initiation through YAP-dependent Aerobic Glycolysis. Hepatology :
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285

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