Josef F. Novak

Biology Department

Contact Information
Biology Building 012B
novak@bucknell.edu
570-577-1286

Educational Background
PhD, Yale University

Dr. Novak has been a Professor in the Department of Biology since 1997. He has taught the following courses: Cell Biology, Endocrinology, Biology of Cancer, and Human Physiology, with associated laboratory exercises. He received a bachelor’s degree from Prague University (Czech Republic) and a PhD degree from Yale University (Department of Biology). As part of his postdoctoral training he served as an Instructor at Princeton University and in the Department of Pharmacology at St. Jude Childrens’ Hospital in Memphis under the direction of Dr. Arnold Welch. He then became a director of an Orthopaedic Research Laboratory devoted to research on osteosarcoma at Allegheny General Hospital, Pittsburgh.

Research Interests
Proenzyme Treatment of Cancer

• The current major research interest is to understand the antitumor and antimetastatic effects of a mixture of purified proenzymes including trypsinogen, chymotrypsinogen and amylase. The treatment is based on a nearly 100-year-old observation made by John Beard at the University of Edinburgh. Although the achievements of Beard have been long forgotten, the renewed interest in the use of macromolecules (i.e., antibodies) against cancer has led us to reconsider the major premises of Beard’s theory. Through the efforts of Dr. Frantisek Trnka, 19 terminal patients pronounced incurable or released from traditional cancer care have been treated with the proenzyme mixture. Eight of these patients responded by a multiyear survival free of the major complications seen with traditional drug therapies. We found that administered proenzymes exert a selective effect on tumor cells in terms of their cell-cell interactions, adherence and motility. In vivo, proenzymes cause increased levels of angiostatic peptides in the blood. The results were recently published:

Novak, JF and Trnka, F. Proenzyme therapy of cancer. Seventh International Conference of Anticancer Research, Corfu , Greece, October 25-30, 2004 (Anticancer Research 24: 3582 (abstr.), 2004.
Novak JF and Trnka, F. Proenzyme therapy of cancer. Anticancer Research 25: 1157-1178, 2005. <download pdf>

Oxytocin and Oxytocin Receptor System

• Classical target organs of oxytocin are myoepithelia of uterus and breast. We established that plasminogen activators can cleave a hexapeptide from the carboxyl end of the bone-specific protein – osteocalcin. Its amino acid sequence was found to be identical to a segment of the oxytocin receptor. Consequently we determined that the hexapeptide can efficiently block the binding and thus the action of oxytocin. As such, the hexapeptide is the only known natural antagonist of the hormone oxytocin. As the oxytocin inhibits the growth of bone cells it is possible that the osteocalcin peptide could be a natural candidate for treatment of human conditions ranging from obstetrics complications to osteoporosis and osteoarthritis.

Novak J. F, Hayes J. D., and Nishimoto S. K. Plasmin-mediated proteolysis of osteocalcin. J. Bone Mineral Res. 12:1035-1042, 1997.
Novak, J. F., Judkins M. B., Chernin M. I., Cassoni P., Bussolati G., Nitche J., and Nishimoto S. K. Osteocalcin-derived hexapeptide interferes with the oxytocin-mediated inhibition of cancer cell – A new mechanism in bone metastasis. Proceedings AACR, 40: 327, 1999
Novak J. F., Judkins M. B., Chernin M. I., Cassoni P., Bussolati G., Nitche J. A., and Nishimoto S. K. A plasmin-derived hexapeptide from the carboxyl end of osteocalcin counteracts oxytocin-mediated growth inhibition of osteosarcoma cells. Cancer Res. 60: 3470-3476, 2000.

• We and others have discovered that both oxytocin and its receptor are produced by many normal and nearly all tumor cells. Recently, we found that the oxytocin receptor is localized into the nuclei as well as the plasma membrane of the tumor cells. Our goal is this novel nuclear hormone/receptor system in neoplastic as well as normal cells and tissues.

Kinsey C. G., Cassoni P., Bussolati G., Kimura T., Chernin M. I., Novak J. F. Oxytocin receptor constitutively localizes to nucleus of osteosarcoma cells. Beatson International Cancer Conference, Glasgow, July 8, 2003.
Kinsey C. G., Cassoni P., Bussolati G., Kimura T., Chernin M. I. and Novak J. F. Constitutive and ligand-induced nuclear localization of oxytocin receptor. Submitted to American journal of physiology, August 2005.

Selected Past Research Interests
•Interactions between a tumor and surrounding normal tissues often determine the course of the neoplastic disease. We studied cell-cell and tumor-stroma relationships in terms of cell surface receptors for TGFb and insulin-like growth factors These components shape the immediate tumor cells’ environment which, in turn, has a decisive role in tumor cell growth or survival. We discovered that the plasminogen activator system in tumor cells is capable of activating latent TGFb and releasing IGFs from complexes with IGF-binding proteins.

Campbell P. G., Novak J. F., Yanosick T. B., McMaster J. H. Involvement of the plasmin system in dissociation of the insulin-like growth factor-binding protein complex. Endocrinology 130:1401-1412, 1991.
Novak J. F. and McMaster J. H. (eds.), "Frontiers in Osteosarcoma Research," Hogrefe and Huber Publishers , Seattle, 1993.
Novak JF, McMaster JH, Campbell PG: Regulation of transforming growth factor beta (TGF-b) binding to TGF-b Type III receptor (betaglycan) in osteosarcoma by plasmin. In: Frontiers in Osteosarcoma Research, JF Novak and JH McMaster (eds.), pp. 525-529, Hogrefe and Huber Publishers, Seattle, 1993.
Campbell P. G., Wines K, Yanosick T. B., and Novak J. F. Binding and activation of plasminogen on the surface of osteosarcoma cells. J Cell Physiol, 159: 1-10, 1994.

•Sequences of a simian SV40 virus were discovered in certain human tumors. The origin of such sequences in human genome are not clear but have been discussed in terms of contamination of Salk polio vaccines with SV40. We have shown that incomplete SV40 genome is sufficient in transformation of cells.

Takahashi M., Chernin M., Yamamoto O., Tonzetich J., Kinsey C. and Novak J.F. Transformation of MC3T3-E1 cells following stress and transfection with pSV2neo plasmid. Anticancer Research, 22: 585-598, 2000.

• The stability of p53 in osteosarcomas of human and mouse origin was studied. The goal of these studies was to establish the role of p53 in bone cell transformation and particularly its effect on expression of bone-specific proteins and differentiation.

Chandar N, Billig B, McMaster J, Novak J: Inactivation of p53 gene in human and murine osteosarcoma cells. Br J Cancer 65: 208-214, 1992.
Chandar N, Campbell P, Novak J, Smith M: Dependence of induction of osteocalcin gene expression on the presence of wild-type p53 in murine osteosarcoma cell line. Molecular Carcinogenesis 8: 299-305, 1993.

The following individuals were part of the efforts of Orthopaedic Research Laboratory (ORL) at Allegheny General Hospital, Pittsburgh, or students/collaborators at Bucknell University. Their names are mentioned with gratitude and appreciation:

ORL Members and Visiting Scientists: (1988-1996)

Kazuo Asanuma, M
David Beidler, PhD
Brenda Billig, BS
Phil Campbell, PhD
Nalini Chandar, PhD
Mitch Chernin, PhD
Hiroshi Fukushima, MD
Jay Hayes, BS
Terry Hentosz,BS
James McMaster,MD
Ken Nishimoto, PhD
Mitsugu Takahashi, MD
Osamu Yamamoto, MD
Tom Yanosick,BS
Mary Yong, BS

Bucknell University Undegraduate Students and Staff: (1996-2004)
Mitch Chernin, PhD
Gianni Bussolati, MD
Paola Cassoni, MD
Carmen Gherghisan, BS
Madelaine Judkins, MS
Tadashi Kimura, MD
Conan Kinsey, BS
Bethany Miller, BS
Jason Nitche, MD
Jaclyn Shull, BS
John Tonzetich, PhD
Frantisek Trnka, MD

Present Students :
Kirsten Elzer
Becky Michaud
Mike Rice-Shesh