Dr. Robert Casero, Jr.
Polyamine Metabolic Pathway
Professor of Oncology
Joint Appointment in Cellular and Molecular Medicine
Joint Appointment in Toxicological Sciences,The Johns Hopkins Bloomberg School of Public Health
Ph.D., Department of Pharmacology, Roswell Park Graduate Division, State University of New York at Buffalo
Postdoctoral Fellow in Oncology The Johns Hopkins University School of Medicine
The primary research goals of the Casero laboratory are to understand the roles of polyamines and polyamine metabolism in neoplastic growth and to develop drugs that target these roles as part of an antineoplastic strategy. Polyamines are naturally occurring polycationic alkyl amines that are absolutely required for normal and tumor cell growth. Consequently, the major focus of the laboratory is to further understand the natural role of the polyamines at the molecular level to facilitate the design of agents that target their metabolism. This work includes the study of the roles of polyamines in cell growth and survival, regulation of gene expression and mechanism of action of antineoplastic polyamine analogues that induce programmed cell death. The mechanisms related to cellular polyamine transport are also of interest to the laboratory.
Considerable work has demonstrated the polyamine metabolic pathway to be a rational target for antineoplastic drug development. The Casero laboratory has made several important contributions to the field in identifying specific targets in the pathway that offer the potential to improve the selectivity of action of newly developed agents. Specifically, it was the first laboratory to describe the superinduction of a rate-limiting enzyme in the polyamine catabolic pathway, spermidine/spermine N1-acetyltransferase (SSAT) and demonstrated that the activity of SSAT was linked to the cytotoxic response to a new class of antitumor polyamine analogues. Based in part on the laboratory’s cloning, examination of the regulation, and demonstration of the selectivity of SSAT induction in important solid tumors in response to these agents, clinical trials are under way examining the potential of these new analogues.
Recently, the laboratory has discovered a completely novel enzyme in the human polyamine catabolic pathway, the inducible spermine oxidase SMO(PAOh1), which produces the reactive oxygen species H2O2 as one of its products. The discovery of this enzyme is particularly relevant for two important reasons: Its inducible activity can be used as a target for selectively killing human tumor cells, and the inappropriate expression of this enzyme may play a direct role in the etiology of specific cancers. Each of these avenues is under active investigation and has considerable potential for both the treatment and prevention of multiple human cancers.
Babbar, N.; Hacker, A.; Huang, Y.; Casero, R.A., Jr. Tumor necrosis factor alpha induces spermidine/spermine N1-acetyltransferase through nuclear factor kappaB in non-small cell lung cancer cells. J Biol Chem. 2006 Aug 25;281(34):24182-24192.
Huang, Y.; Keen, J.C.; Pledgie, A.; Marton, L.J.; Zhu, T.; Sukumar, S.; Park, B.H.; Blair, B.; Brenner, K.; Casero, R.A., Jr.; Davidson, N.E. Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. J Biol Chem. 2006 Jul 14;281(28):19055-19063.
Wang, Y.; Casero, R.A., Jr. Mammalian polyamine catabolism: a therapeutic target, a pathological problem, or both? J Biochem (Tokyo). 2006 Jan;139(1):17-25.
Babbar, N.; Murray-Stewart, T.; Casero, R.A., Jr. Inflammation and polyamine catabolism: the good, the bad and the ugly. Biochem Soc Trans. 2007 Apr;35(Pt 2):300-304.
Casero, R.A., Jr.; Marton, L.J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov. 2007 May;6(5):373-390.
Huang, Y.; Greene, E.; Murray Stewart, T.; Goodwin, A.C.; Baylin, S.B.; Woster, P.M.; Casero, R.A., Jr. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8023-8028.
Rider, J.E.; Hacker, A.; Mackintosh, C.A.; Pegg, A.E.; Woster, P.M.; Casero, R.A., Jr. Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide. Amino Acids. 2007 Aug;33(2):231-240.
Goodwin, A.C.; Jadallah, S.; Toubaji, A.; Lecksell, K.; Hicks, J.L.; Kowalski, J.; Bova, G.S.; De Marzo, A.M.; Netto, G.J.; Casero, R.A., Jr. Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues. Prostate. 2008 May 15;68(7):766-772.
Hacker, A.; Marton, L.J.; Sobolewski, M.; Casero, R.A., Jr. In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells. Cancer Chemother Pharmacol. 2008 Dec;63(1):45-53.
Murray-Stewart, T.; Wang, Y.; Goodwin, A.; Hacker, A.; Meeker, A.; Casero, R.A., Jr. Nuclear localization of human spermine oxidase isoforms - possible implications in drug response and disease etiology. Febs J. 2008 Jun;275(11):2795-2806.
Casero, R.A.; Pegg, A.E. Polyamine catabolism and disease. Biochem J. 2009 Aug 1;421(3):323-338.
Casero, R.A., Jr.; Woster, P.M. Recent advances in the development of polyamine analogues as antitumor agents. J Med Chem. 2009 Aug 13;52(15):4551-4573.
Huang, Y.; Marton, L.J.; Woster, P.M.; Casero, R.A. Polyamine analogues targeting epigenetic gene regulation. Essays Biochem. 2009;46:95-110.
Huang, Y.; Stewart, T.M.; Wu, Y.; Baylin, S.B.; Marton, L.J.; Perkins, B.; Jones, R.J.; Woster, P.M.; Casero, R.A., Jr. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res. 2009 Dec 1;15(23):7217-7228.
Senanayake, M.D.; Amunugama, H.; Boncher, T.D.; Casero, R.A.; Woster, P.M. Design of polyamine-based therapeutic agents: new targets and new directions. Essays Biochem. 2009;46:77-94.
Belinsky, S.A.; Grimes, M.J.; Picchu, M.A.; Michell, H.D.; Stidley, C.A.; Tesfaigzi, Y.; Channel, M.M.; Liu, Y.; Casero, R.A.; Baylin, S.B.; Reed, M.D.; Tellez, C.S.; March, T.H. Targeting the epigenome for lung cancer therapy. Cancer Research. 2010;In Press.
Cervelli, M.; Bellavia, G.; Fratini, E.; Amendola, R.; Polticelli, F.; Barba, M.; Federico, R.; Signore, F.; Gucciardo, G.; Grillo, R.; Woster, P.M.; Casero, R.A., Jr.; Mariottini, P. Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm. BMC Cancer. 2010;10:555
Chaturvedi, R.; Asim, M.; Hoge, S.; Lewis, N.D.; Singh, K.; Barry, D.P.; de Sablet, T.; Piazuelo, M.B.; Sarvaria, A.R.; Cheng, Y.; Closs, E.I.; Casero, R.A., Jr.; Gobert, A.P.; Wilson, K.T. Polyamines Impair Immunity to Helicobacter pylori by Inhibiting L-Arginine Uptake Required for Nitric Oxide Production. Gastroenterology. 2010 Nov;139(5):1686-1698, 1698 e1681-1686.
Goodwin, A.C.; Murray-Stewart, T.; Casero, R.A. A simple assay for mammalian spermine oxidase: a polyamine catabolic enzyme implicated in drug response and disease. . In: Casero, R.A.; Pegg, A.E., editors, Methods in Molecular Biology, Polyamines-Methods and Protocols: Springer; 2010.
Hakkinen, M.R.; Hyvonen, M.T.; Auriola, S.; Casero, R.A., Jr.; Vepsalainen, J.; Khomutov, A.R.; Alhonen, L.; Keinanen, T.A. Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases. Amino Acids. 2010 Feb;38(2):369-381
Healey, M.A.; Deaton, S.L.; Alder, J.K.; Winnepenninckx, V.; Casero, R.A., Jr.; Herman, J.G. Id1 overexpression is independent of repression and epigenetic silencing of tumor suppressor genes in melanoma. Epigenetics. 2010 Jul 1;5(5):410-421
Hong, S.K.; Chaturvedi, R.; Piazuelo, M.B.; Coburn, L.A.; Williams, C.S.; Delgado, A.G.; Casero, R.A., Jr.; Schwartz, D.A.; Wilson, K.T. Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm Bowel Dis. 2010 Sep;16(9):1557-1566.
Lee, S.B.; Park, J.H.; Woster, P.M.; Casero, R.A., Jr.; Park, M.H. Suppression of exogenous gene expression by spermidine/spermine N1-acetyltransferase 1 (SSAT1) cotransfection. J Biol Chem. 2010 May 14;285(20):15548-15556.
Pledgie-Tracy, A.; Billam, M.; Hacker, A.; Sobolewski, M.D.; Woster, P.M.; Zhang, Z.; Casero, R.A.; Davidson, N.E. The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines. Cancer Chemother Pharmacol. 2010 May;65(6):1067-1081.
Sharma, S.K.; Wu, Y.; Steinbergs, N.; Crowley, M.L.; Hanson, A.S.; Casero, R.A.; Woster, P.M. (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J Med Chem. 2010 Jul 22;53(14):5197-5212.
Zahedi, K.; Huttinger, F.; Morrison, R.; Murray-Stewart, T.; Casero, R.A.; Strauss, K.I. Polyamine catabolism is enhanced after traumatic brain injury. J Neurotrauma. 2010 Mar;27(3):515-525.