Traditional means of treating cancer have been surgery, radiation, and chemotherapy. Recently, novel therapeutic strategies like hyperthermia and heat shock protein (HSP)-based cancer therapies have shown great potential. However, the mechanism by which HSPs elicit anti-tumor immunity is thus far incompletely understood. This application will address this gap in the knowledge base by elucidating the cellular activation mechanism induced by extracellular HSP70. The objective of this particular application, which is the next step towards attainment of our long-term goal, is to understand how extracellular HSP70 activates immune responses with special emphasis on mechanisms of anti-tumor immunity. The central hypothesis proposed in this application is that HSP70 found in the extracellular milieu or expressed on tumors act as both chaperone and cytokine, a chaperokine, activates cells of the innate immune system, resulting in the launching of non-specific killing mechanisms within the tumor microenvironment. The rationale for the proposed research is that, once understanding has been obtained regarding mechanisms of HSP70-induced cellular activation, it is expected that it will become possible to enhance HSP-based cancer therapies by targeting important signal transduction intermediates, either pharmacologically or through molecular biological strategies. We plan to test our central hypothesis and accomplish the overall objective of this application by pursuing the following 3 specific aims: 1) To study signal transduction pathways activated by extracellular HSP70, 2) To biochemically characterize and identify the HSP70 surface receptor and, 3) To study the biological consequence of extracellular HSP70 and its role in hyperthermia-induced tumor killing. Successful completion of these studies will allow fundamental new knowledge to be obtained that is expected to significantly advance the general field of heat shock protein research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA091889-01A2
Application #
6573245
Study Section
Special Emphasis Panel (ZRG1-MEP (03))
Program Officer
Wong, Rosemary S
Project Start
2003-03-21
Project End
2007-02-28
Budget Start
2003-03-21
Budget End
2004-02-28
Support Year
1
Fiscal Year
2003
Total Cost
$287,470
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Rosas, Paola C; Nagaraja, Ganachari M; Kaur, Punit et al. (2016) Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment. PLoS One 11:e0149409
Nagaraja, Ganachari M; Kaur, Punit; Neumann, William et al. (2012) Silencing Hsp25/Hsp27 gene expression augments proteasome activity and increases CD8+ T-cell-mediated tumor killing and memory responses. Cancer Prev Res (Phila) 5:122-37
Panossian, Alexander; Wikman, Georg; Kaur, Punit et al. (2012) Adaptogens stimulate neuropeptide y and hsp72 expression and release in neuroglia cells. Front Neurosci 6:6
Siepermann, Meinolf; Koscielniak, Ewa; Dantonello, Tobias et al. (2012) Oral low-dose chemotherapy: successful treatment of an alveolar rhabdomyosarcoma during pregnancy. Pediatr Blood Cancer 58:104-6
Nagaraja, G M; Kaur, P; Asea, A (2012) Role of human and mouse HspB1 in metastasis. Curr Mol Med 12:1142-50
Kaur, Punit; Asea, Alexzander (2011) Quantitation of heat-shock proteins in clinical samples using mass spectrometry. Methods Mol Biol 787:165-88
Kaur, Punit; Nagaraja, Ganachari M; Asea, Alexzander (2011) Combined lentiviral and RNAi technologies for the delivery and permanent silencing of the hsp25 gene. Methods Mol Biol 787:121-36
Zheng, Hongying; Nagaraja, Ganachari M; Kaur, Punit et al. (2010) Chaperokine function of recombinant Hsp72 produced in insect cells using a baculovirus expression system is retained. J Biol Chem 285:349-56
Hurwitz, Mark D; Kaur, Punit; Nagaraja, Ganachari M et al. (2010) Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer. Radiother Oncol 95:350-8
Kaur, Punit; Reis, Michael D; Couchman, Glen R et al. (2010) SERPINE 1 Links Obesity and Diabetes: A Pilot Study. J Proteomics Bioinform 3:191-199

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