Prostate cancer, Retinoblastoma (RB) /E2F, calpain, androgen receptor, breast cancer

Prostate carcinoma is the most commonly diagnosed cancer in men, and the second leading cause of death due to cancer in Western civilization. Androgen ablation therapy is effective in treating androgen-dependent tumors, but eventually, androgen-independent tumors recur and are refractory to conventional chemotherapies. Hence, the emergence of androgen independence is the most challenging problem in managing prostate tumors.

Calpain mediated Androgen Receptor Cleavage as a Mechanism for Androgen Independence.

We have identified a novel mechanism of androgen independence: calpain cleaves the androgen receptor (AR) into a constitutively active, androgen-independent isoform. Calpain proteolysis removes the C-terminal ligand binding domain (LBD) of the AR generating a constitutively active 80 KDa molecule. An analysis of human prostate tumors indicates that some tumors express higher levels of a 80KDa truncated AR than non-cancerous prostate tissue. Two androgen independent cell lines, R1 and Rv1 express high levels of the truncated AR and serve as a model to studying these phenomena. Interestingly, treatment of these cells with the calpain inhibitor calpeptin reduces the level of the truncated receptor and treatment of the RV1 cells with calpeptin in the absence of androgens induces apoptosis.  Recent studies have revealed an intricate network between calpain, AR and other prominent signaling pathways that are often deregulated in tumorigenesis. (Libertini at al, 2007, Cancer Research; Devlin and Mudryj, 2008, Cancer Letters). Current studies are focused on identifying mechanisms that result in elevation of calpain activity and in defining the consequences of increase calpain proteolysis on cell physiology. 

Deregulation of the E2F/RB pathway in prostate cancer.
The Rb/E2F pathway regulates multiple cellular processes including proliferation and apoptosis. RB, the first described tumor suppressor, is mutated or deleted in some prostate tumors. Additionally, E2F3, a member of the E2F family, is overexpression in some prostate tumors and E2F3 overexpression is an independent prognostic marker of a poor clinical outcome.  In previous studies we have overexpressed E2F1 in androgen-dependent prostate cells. E2F1 overexpressing cells fail to undergo a growth arrest in androgen depleted media, are more sensitive to the apoptotic agent etoposide and have altered expression of multiple genes (Libertini et al, 2006, Prostate). Our current studies are defining the role of E2F3 in prostate cancer etiology, growth, acquisition of androgen independence, migration and invasion, and sensitivity to chemotherapeutics.

Hong-Lin Devlin and Maria Mudryj. Progression of Prostate Cancer: Multiple Pathways to Androgen Independence.  (2008) Cancer Letters in press.

Honglin Devlin, Phillip C. Mack, Rebekah A. Burich, Paul H. Gumerlock, Hsing-Jien Kung, Maria Mudryj and  Ralph W. deVere White. (2008) Impairment of the DNA Repair and Growth Arrest Pathways by p53R2 Silencing Enhances DNA Damage-Induced Apoptosis in a p53 Dependent Manner in Prostate Cancer (CaP) Cells. Molecular Cancer Research 6 (5), 808-818.

Maria Mudryj, Elizabeth Reay, Satya Dandekar, Laurel Beckett, Ralph DeVere White and Regina Gandour-Edwards. (2007) A novel p53/p130 axis in bladder tumors. Urology 70, 608-12.

Stephen Libertini, Clifford G. Tepper, Veronica Rodriguez, David M. Asmuth, Hsing-Jien Kung and Maria Mudryj. (2007) Evidence for Calpain mediated Androgen Receptor Cleavage as a Mechanism of Androgen Independence and Potential Therapeutic Target in Prostate Tumors. Cancer Research 69, 9001-5.

Stephen Libertini, Clifford G. Tepper, Moraima Guadalupe, Ying Lu, David M. Asmuth and Maria Mudryj. (2006) E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis. Prostate 66, 70-81.

Stephen J. Libertini, Brian Robinson, Navdeep K. Dhillon, Danielle Glick, Michael George, Satya Dandekar, Jeffrey P. Gregg, Earl Sawai, and Maria Mudryj. (2005) Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype. Cancer Research 65, 10700-10708.

Dhillon, N.K., and Maria Mudryj. (2003) Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells. Genes and Immunity 4, 336-342.

Hau Nguyen, Maria Mudryj, Moraima Guadalupe and Satya Dandekar. (2003) Hepatitis C virus core protein expression leads to biphasic regulation of the p21 cdk inhibitor and modulation of hepatocyte cell cycle. Virology 312, 245-253.

Ndolo, T., N.K. Dhillon, H. Nguyen, M. Guadalupe, Maria Mudryj, and S. Dandekar. (2002) Simian immunodeficiency virus nef protein delays the progression of CD4 + T cells through G 1/S phase of the cell cycle. Journal of Virology 76:3587-3595.

Dhillon, N.K., and Maria Mudryj. (2002) Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest. Oncogene 21:4626-34.

DeBorja, P., Collins, N.K., Du, P., Azizkhan-Clifford, J.C., Mudryj, M. (2001) Cyclin A/CDK2 phosphorylates Sp1 and enhances Sp1 mediated transcription. EMBO Journal 20:5737-5747.

Tepper, C.G., Seldin, M.F., Mudryj, M. (2000) Fas mediated apoptosis of proliferating, transiently growth arrested and senescent normal human fibroblasts. Experimental Cell Research 260, 9-19.