Salvatore Pizzo, MD, PhD

Chair, Department of Pathology

Department / Division:
Pathology / Pathology

Address:
DUMC 3712
Durham, NC 27710

Office Telephone:
919-684-3528

Fax Telephone:
919-684-8689

• MD, Duke University School of Medicine, 1973

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

• 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.

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.  Mol Cancer Ther.  2009 May 5. (2009) 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.  Nat Med.  2008 May;14(5):536-41. (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.  J Immunol.  2008 Jul 1;181(1):364-73. (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.  Mol Psychiatry.  2007 Aug 28. (2007) 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.  J Biol Chem.  2007 Nov 9;282(45):32811-20. (2007) 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.  J Leukoc Biol.  2007 Oct 29. (2007) 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.  J Biol Chem.  2006 May 12;281(19):13694-707. (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 Res.  2006 Dec 1;66(23):11424-31. (2006) 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 Res.  2006 Jan 15;66(2):875-82. (2006) 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.  J Immunol.  2005 Aug 15;175(4):2525-33. (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.  J Biol Chem.  2005 Nov 18;280(46):38276-89. (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.  J Immunol.  2005 Feb 15;174(4):2092-7. (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.  J Biol Chem.  2005 Jul 15;280(28):26278-86. (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.  J Biol Chem.  2005 Jul 22;280(29):27173-8. (2005) 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.  J Biol Chem.  2005 Jan 21;280(3):1740-5. (2005) 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. J Immunol. 2004 Jan 1;172(1):70-8. (2004) Abstract

Berwin B, Delneste Y, Lovingood RV, Post SR, Pizzo SV. SREC-I, a type F scavenger receptor, is an endocytic receptor for calreticulin.  J Biol Chem.  2004 Dec 3;279(49):51250-7. (2004) 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.  Nat Immunol.  2003 Dec;4(12):1199-205. (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.  J Biol Chem.  2003 Jul 18;278(29):27312-8. (2003) 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.  EMBO J.  2003 Nov 17;22(22):6127-36. (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.  Proc Natl Acad Sci U S A.  2001 Jun 5;98(12):6656-61. (2001) 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. Cell Signal. 2000 Feb;12(2):99-104. (2000) 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. J Biol Chem. 2000 Sep 1;275(35):26806-11. (2000) Abstract

Wu SM, Pizzo SV. Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin. Biochemistry. 1999 Oct 19;38(42):13983-90. (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. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2811-6. (1999) 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. J Biol Chem. 1999 Sep 3;274(36):25785-91. (1999) Abstract

Bowers, E.V., Horvath, J.J., Bond, J.E., Cianciolo, G.J., and Pizzo, S.V.:  Antigen Delivery by Alpha-2-Macroglobulin Enhances the Cytotoxic T Lymphocyte Response.  J Leuk. Biol., in press, 2009.