Prostate cancer patients diagnosed with late-stage, distant-metastatic disease have a dismal 28% 5- year survival rate; particularly in contrast to the 100% 5-year survival rate of local and regional disease. Considering the fact that prostate cancer is the most common cancer among men in the United States, and the second most common worldwide, effective therapies for treating metastatic prostate cancer remains a significant unmet clinical need. This proposal aims to identify a novel therapeutic target to treat metastatic prostate cancer by elucidating the role of ferroportin, the only known iron export protein in mammals, in the metastatic spread of prostate cancer. Ferroportin is the only known iron export protein in vertebrates and is a key mechanism for regulating cellular and systemic iron levels. This protein is part of a regulatory axis, with its negative regulator hepcidin, that controls iron levels. This regulatory axis is disturbed in cancer cells which exhibit elevated iron levels, reduced ferroportin levels, and increased hepcidin relative to normal tissue. Emerging evidence suggests that iron plays a critical role in metastatic processes. Through regulation of iron, so too may ferroportin. Analysis of patient samples does indeed indicate that ferroportin is differentially regulated in normal, primary tumor tissue, and metastatic tumor tissue. This proposal investigates mechanisms by which ferroportin expression may regulate the metastatic spread of prostate cancer.
Aim 1 tests the hypothesis that ferroportin expression regulates cellular motility and invasiveness. Motility is studied phenotypically by gap closure assays and transwell motility assays. Invasion is assessed by transwell invasion assays. Potential mechanisms include the iron-regulated metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), matrix metalloproteinases and serine proteinases.
Aim 2 tests the hypothesis that ferroportin regulates cancer cell viability at the metastatic site. NDRG1 and cell cycle regulators p21 and p38 are investigated as mechanisms. The phenotype of ferroportin overexpression will be assessed in vivo by evaluation of intratibial tumor growth, development of bone lesions, and by proliferative markers.
|Torti, Suzy V; Manz, David H; Paul, Bibbin T et al. (2018) Iron and Cancer. Annu Rev Nutr 38:97-125|
|Lemler, David J; Lynch, Miranda L; Tesfay, Lia et al. (2017) DCYTB is a predictor of outcome in breast cancer that functions via iron-independent mechanisms. Breast Cancer Res 19:25|
|Paul, Bibbin T; Manz, David H; Torti, Frank M et al. (2017) Mitochondria and Iron: current questions. Expert Rev Hematol 10:65-79|
|Deng, Zhiyong; Manz, David H; Torti, Suzy V et al. (2017) Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth. Oncotarget 8:82231-82243|