Frank Torti Lab
The prevention and treatment of cancer is intimately linked to the cellular and organismal interaction of cancer cells with their microenvironment. Dr. Torti’s laboratory focuses on the regulation of key proteins that modify the ability of cancer cells to grow and metastasize. Cellular iron is central to this ability. Iron catalyzes the conversion of hydrogen peroxide into hydroxyl radicals, which then can directly damage cellular constituents. However, iron is not only toxic to cells, but is also essential for the function of enzymes that participate in numerous critical cellular growth processes. These include cell cycling, reductive conversion of ribonucleotides to deoxyribonucleotides, ATP generation via electron transfer, and others. Not surprisingly, iron homeostasis is tightly regulated.
Ferritin, the primary intracellular iron-binding protein that limits free iron availability in cells and ferroportin, the only known exporter of ferrous iron, are critical mediators of cellular protection against free radical injury. Dr. Torti’s laboratory has demonstrated the molecular details of the regulation of ferritin by inflammatory cytokines such as tumor necrosis factor (TNF) and IL-1 (interleukin-1). His lab has also elucidated the molecular basis of the ferritin regulation by pro-oxidant stress, including that induced by environmental toxins. The cellular and organismal consequence for cancer development of dysregulation of the proteins of iron metabolism is a major area of research in Dr. Torti’s laboratory.
Recently, research in the laboratory of Dr. Torti has shown a previously unidentified link between the iron export protein ferroportin and breast cancer on both a cellular and molecular level and also human breast cancer patients. What fundamental regulatory mechanisms that underlie this observation? Can the use of testing for individual variation in levels of proteins of iron metabolism such as ferroportin be used clinically to patient predict outcome and direct cancer therapy? These are a few of the questions now being addressed in his laboratory.
Select Publications
Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM. Phase I and Pharmacokinetic Study of Angiotensin-(1-7), an Endogenous Antiangiogenic Hormone. Clin Cancer Res (23):7398–404, 2009. PMID: 19920106
Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, Torti SV. A general map of iron metabolism and tissue-specific subnetworks. Mol BioSyst 5(5): 422 - 443, 2009.
Coffman LG, Parsonage D, D’Agostino R Jr, Torti FM, Torti SV. Regulatory Effects of Ferritin on Angiogenesis. Proc Natl Acad Sci 106(2): 570-575, 2009.
[Editorial commentary: De Domenico I, McVey Ward D, Kaplan J. Serum ferritin regulates blood vessel formation: A role beyond iron storage. Proc Natl Acad Sci 106(6): 1683-1684, 2009.
Jiao Y, Wilkinson J, Di X, Wang W, Hatcher H, Kock ND, D’Agostino R, Knovich MA, Torti FM, Torti SV. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 113(2): 462-469, 2009.
Coffman LG, Brown JC, Johnson DA, Parthasarathy N, D’Agostino RB Jr, Lively MO, Hua X, Tilley SL, Muller-Esterl W, Willingham MC, Torti FM, Torti SV. Cleavage of High Molecular Weight Kininogen by Elastase and Tryptase is Inhibited by Ferritin. Am J Physiol Lung Cell Mol Physiol 294: 505-515, 2008.
Stadler WM, Desai AA, Quinn DI, Bukowski R, Poiesz B, Kardinal CG, Lewis N, Makalinao A, Murray P, Torti FM. A Phase I/II Study of GTI-2040 and Capecitabine in Patients with Renal Cell Carcinoma. Ca Chemo Pharm 61(4): 689-694, 2008.
Torti SV, Byrne F, Whelan O, Levi N, Ucer B, Schmid M, Torti FM, Akman S, Liu J, Ajayan PM, Nalamasu O, Carroll DL. Thermal Ablation Therapeutics based on CNx Multi-Walled Nanotubes. International Journal of Nanomedicine 2(3):1-8, 2007.
Blish K, Wang W, Willingham M, Du W, Birse CE, Krishnan SR, Brown JC, Hawkins GA, Garvin AJ, D’Agostino RB, Torti FM, Torti SV. A Human Bone Morphogenetic Protein Antagonist is Downregulated in Renal Cancer. Mol. Biol. Cell 19: 457-464, 2008.