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.
View all on Pubmed
1) Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A., and Shi, Y. Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1. Cell 119:941-953, 2004.
2) Huang, Y., Greene, E., Stewart, T.M., Goodwin, A.C., Baylin, S.B., Woster, P.M., and Casero, R.A., Jr. Inhibition of the Lysine Specific Demethylase, LSD1, by Novel Polyamine Analogues Results in Re-Expression of Aberrantly Silenced Genes. Proc Natl Acad Sci USA 104:8023-8028, 2007.
3) Wang, Y., Devereux, W., Woster, P.M., Murray Stewart, T., Hacker, A., and Casero, R.A., Jr. Cloning and Characterization of the Human Polyamine Oxidase that is Inducible by Polyamine Analogue Exposure. Cancer Res. 61:5370-5373, 2001.
4) Goodwin, A.C., Wu, S., Huso, D.L., Wu, X., Destefano Shields, C.E., Hacker-Prietz, A., Rabizadeh, S., Sears, C.L., and Casero, R.A. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl. Acad. Sci USA, 108(37):15354-9. 2011. PMCID: PMC3174648.
5) Murray-Stewart, T., Sierra, J.C., Piazuelo, M.B., Mera, R.M., Chaturvedi, R., Bravo, L.E., Correa, P., Schneider, B.G., Wilson, K.T., and Casero, R.A. miR-124 methylation contributes to Helicobacter pylori-induced gastric carcinogenesis by preventing spermine oxidase regulation. Oncogene. In press, DOI: 10.1038/onc.2016.91, 2016. NIHMS# 749206