Physicians

Chair, Department of Pathology

Department / Division
Pathology / Pathology - General

Address
DUMC 3712
Durham, NC 27710

Office Telephone
919-684-3528

Fax Telephone
919-684-8689

Training

• MD, Duke University School of Medicine, 1973

Residency

• Pathology, Duke University Medical Center, 1973-1976
• Medicine, Duke University Medical Center, 1976-1979

Other Training

• PhD, Biochemistry, Duke University, 1973

Clinical Interests
Coagulation, biochemistry, serum and electrophoresis, immunoelectrophoresis

Research Interests
RESEARCH ABSTRACT
The laboratory pursues a number of projects in which proteolytic events play major roles in cell biology. This includes angiogenesis, regulation of cellular growth, and immune regulation. Folkman and colleagues demonstrated angiostatin, a proteolytic fragment of plasminogen/plasmin, inhibits endothelial cell growth thus causing the death of tumors. In 1999, we first identified cell surface-associated ATP synthase as the angiostatin receptor. Subsequently, we demonstrated that the molecule is fully functional, generating ATP on the external plasma membrane leaflet. Angiostatin binds to the catalytic β-subunit of the synthase inhibiting ATP synthesis and also the translocation of H+ in the direction of ATP synthesis. This is of little consequence to endothelial cells at neutral pH; however, at low pH which is typical of the tumor microenvironment, the inability of H+ to move out of the cell causes the internal pH of these cells to fall to 6.5 and the endothelial cells then die. Recently, we have shown that ATP synthase is also on the surface of a number of tumor cells and angiostatin kills these cells directly by the same mechanism at low environmental pH. We have also shown that antibodies targeting the catalytic β-subunit of the synthase are angiostatin-mimetics. In addition a group of stillbenes found in grapes, hence red wine, by directly inhibiting the synthase in part explains the reported beneficial effects of red wines/grape juice.

Studies from this laboratory identified cell surface expression of the molecular chaperone GRP78 as a major factor in prostate cancer and other malignancies. Cell surface GRP78 functions as a signaling receptor promoting tumor proliferation and suppressing apoptosis. Patients with a number of malignancies mount an autoimmune response to GRP78 and these antibodies,which bind to the NH₂ terminal domains of GRP78, are receptor agonists whose appearance is a marker of poor prognosis. More recently, we have shown that antibodies directed against the COOH-terminal domain of GRP78 are receptor antagonists which may have therapeutic potential for treating patients whose tumors express GRP78 on the cell surface.

Industry Relationships and Collaborations (What's this?)

This faculty member has no reported relationships with industry.

Representative Publications
Misra, UK; Mowery, Y; Kaczowka, S; Pizzo, SV. Ligation of cancer cell surface GRP78 with antibodies directed against its COOH-terminal domain up-regulates p53 activity and promotes apoptosis. Molecular Cancer Therapeutics. 2009;8:1350-1362. (2009) Abstract

Anderson, RB; Cianciolo, GJ; Kennedy, MN; Pizzo, SV. Alpha 2-macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism. Journal of Leukocyte Biology. 2008;83:381-392. (2008) Abstract

Lillis, AP; Greenlee, MC; Mikhailenko, I; Pizzo, SV; Tenner, AJ; Strickland, DK; Bohlson, SS. Murine low-density lipoprotein receptor-related protein 1 (LRP) is required for phagocytosis of targets bearing LRP ligands but is not required for C1q-triggered enhancement of phagocytosis. Journal of Immunology. 2008;181:364-373. (2008) Abstract

McLachlan, JB; Shelburne, CP; Hart, JP; Pizzo, SV; Goyal, R; Brooking-Dixon, R; Staats, HF; Abraham, SN. Mast cell activators: a new class of highly effective vaccine adjuvants. Nature Medicine. 2008;14:536-541. (2008) Abstract

Schmidt, C; Lepsverdize, E; Chi, SL; Das, AM; Pizzo, SV; Dityatev, A; Schachner, M. Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Molecular Psychiatry. 2008;13:953-969. (2008) Abstract

Gonzalez-Gronow, M; Kaczowka, SJ; Payne, S; Wang, F; Gawdi, G; Pizzo, SV. Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or the voltage-dependent anion channel. Journal of Biological Chemistry. 2007;282:32811-32820. (2007) Abstract

Chi, SL; Pizzo, SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Research. 2006;66:875-882. (2006) Abstract

Gonzalez-Gronow, M; Cuchacovich, M; Llanos, C; Urzua, C; Gawdi, G; Pizzo, SV. Prostate cancer cell proliferation in vitro is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum. Cancer Research. 2006;66:11424-11431. (2006) Abstract

Misra, UK; Deedwania, R; Pizzo, SV. Activation and cross-talk between Akt, NF-kappaB, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. Journal of Biological Chemistry. 2006;281:13694-13707. (2006) Abstract

Burwick, NR; Wahl, ML; Fang, J; Zhong, Z; Moser, TL; Li, B; Capaldi, RA; Kenan, DJ; Pizzo, SV. An Inhibitor of the F1 subunit of ATP synthase (IF1) modulates the activity of angiostatin on the endothelial cell surface. Journal of Biological Chemistry. 2005;280:1740-1745. (2005) Abstract

Gonzalez-Gronow, M; Misra, UK; Gawdi, G; Pizzo, SV. Association of plasminogen with dipeptidyl peptidase IV and Na+/H+ exchanger isoform NHE3 regulates invasion of human 1-LN prostate tumor cells. Journal of Biological Chemistry. 2005;280:27173-27178. (2005) Abstract

Misra, UK; Deedwania, R; Pizzo, SV. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. Journal of Biological Chemistry. 2005;280:26278-26286. (2005) Abstract

Misra, UK; Gonzalez-Gronow, M; Gawdi, G; Pizzo, SV. The role of MTJ-1 in cell surface translocation of GRP78, a receptor for alpha 2-macroglobulin-dependent signaling. Journal of Immunology. 2005;174:2092-2097. (2005) Abstract

Misra, UK; Pizzo, SV. Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. Journal of Biological Chemistry. 2005;280:38276-38289. (2005) Abstract

Misra, UK; Sharma, T; Pizzo, SV. Ligation of cell surface-associated glucose-regulated protein 78 by receptor-recognized forms of alpha 2-macroglobulin: activation of p21-activated protein kinase-2-dependent signaling in murine peritoneal macrophages. Journal of Immunology. 2005;175:2525-2533. (2005) Abstract

Berwin, B; Delneste, Y; Lovingood, RV; Post, SR; Pizzo, SV. SREC-I, a type F scavenger receptor, is an endocytic receptor for calreticulin. Journal of Biological Chemistry. 2004;279:51250-51257. (2004) Abstract

Hart, JP; Gunn, MD; Pizzo, SV. A CD91-positive subset of CD11c+ blood dendritic cells: characterization of the APC that functions to enhance adaptive immune responses against CD91-targeted antigens. Journal of Immunology. 2004;172:70-78. (2004) Abstract

Berwin, B; Hart, JP; Rice, S; Gass, C; Pizzo, SV; Post, SR; Nicchitta, CV. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. The EMBO Journal. 2003;22:6127-6136. (2003) Abstract

Gonzalez-Gronow, M; Kalfa, T; Johnson, CE; Gawdi, G; Pizzo, SV. The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells. Journal of Biological Chemistry. 2003;278:27312-27318. (2003) Abstract

McLachlan, JB; Hart, JP; Pizzo, SV; Shelburne, CP; Staats, HF; Gunn, MD; Abraham, SN. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nature Immunology. 2003;4:1199-1205. (2003) Abstract

Moser, TL; Kenan, DJ; Ashley, TA; Roy, JA; Goodman, MD; Misra, UK; Cheek, DJ; Pizzo, SV. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proceedings of the National Academy of Sciences of USA. 2001;98:6656-6661. (2001) Abstract

Bhattacharjee, G; Asplin, IR; Wu, SM; Gawdi, G; Pizzo, SV. The conformation-dependent interaction of alpha 2-macroglobulin with vascular endothelial growth factor. A novel mechanism of alpha 2-macroglobulin/growth factor binding. Journal of Biological Chemistry. 2000;275:26806-26811. (2000) Abstract

Misra, UK; Gawdi, G; Pizzo, SV. Potentiation of calcium levels by extracellular arachidonic acid in nuclei isolated from macrophages stimulated with receptor-recognized forms of alpha(2)-macroglobulin. Cellular Signalling. 2000;12:99-104. (2000) Abstract

Misra, UK; Gawdi, G; Gonzalez-Gronow, M; Pizzo, SV. Coordinate regulation of the alpha(2)-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor by insulin. Journal of Biological Chemistry. 1999;274:25785-25791. (1999) Abstract

Moser, TL; Stack, MS; Asplin, I; Enghild, JJ; Højrup, P; Everitt, L; Hubchak, S; Schnaper, HW; Pizzo, SV. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proceedings of the National Academy of Sciences of USA. 1999;96:2811-2816. (1999) Abstract

Wu, SM; Pizzo, SV. Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin. Biochemistry. 1999;38:13983-13990. (1999) Abstract