The broad focus of Dr. Nicholas Cacalano's laboratory is basic mechanisms of signal transduction, how normal signaling becomes corrupted in cancer and how knowledge of signaling pathways can be exploited for the identification of novel biomarkers of radiation resistance and targets for molecular therapies.
Specifically, they are interested in the role of epigenetic silencing (methylation) of tumor suppressor (Ts) genes in the development of cancer and the acquisition of radiation resistance, determining the mechanism of gene silencing and identifying therapeutics that can re-activate the genes to sensitize cells to radiotherapy.
Cacalano's laboratory has also identified a novel pathway that regulates the DNA damage response. They have shown that Suppressor of Cytokine Signaling (SOCS)-3 has a radioprotective effect in normal cells and tumors, and that in cells lacking SOCS3 the DNA damage response is defective. They are interested in identifying the molecular basis of SOCS3-mediated radioprotection and determining if human tumors that silence SOCS3 epigenetically are radiosensitive due to defects in the DNA damage response.
Thus, it is possible that SOCS3 is a biomarker of radiation resistance in solid tumors, and a potential target of molecular therapeutics.
Sitko JC, Yeh B, Kim M, Zhou H, Takaesu G, Yoshimura A, McBride WH, Jewett A, Jamieson CA, Cacalano NA. SOCS3 regulates p21 expression and cell cycle arrest in response to DNA damage. Cell Signal. 2008 Dec;20(12):2221-30. Epub 2008 Aug 23.
Cacalano NA, Le D, Paranjpe A, Wang MY, Fernandez A, Evazyan T, Park NH, Jewett A. Regulation of IGFBP6 gene and protein is mediated by the inverse expression and function of c-jun N-terminal kinase (JNK) and NFkappaB in a model of oral tumor cells. Apoptosis. 2008 Dec;13(12):1439-49.
Zhou H, Miki R, Eeva M, Fike FM, Seligson D, Yang L, Yoshimura A, Teitell MA, Jamieson CA, Cacalano NA. Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clin Cancer Res. 2007; 13:2344-2353.
Sitko JC, Guevara CI, Cacalano NA. Tyrosine-phosphorylated SOCS3 interacts with the Nck and Crk-L adapter proteins and regulates Nck activation. J Biol Chem. 2004; 279:37662-37669.
Haan S, Ferguson P, Sommer U, Hiremath M, McVicar DW, Heinrich PC, Johnston JA, Cacalano NA. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J Biol Chem. 2003; 278:31972-31979.