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Our research efforts span the basic and the clinical sciences. In the laboratory, our work focuses on understanding the process of renal and prostatic carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers. As part of our work, we explore the role of zinc in development and progression of prostate malignancy.  Zinc concentrations diminish early in the course of prostate carcinogenesis -- prior to histopathological changes -- and continue to decline during progression toward castration-resistant growth.  The objective of research in our laboratory is to test and advance an emerging paradigm that intracellular zinc deficiency augments malignant potential of prostate cancer cells and, therefore, promotes prostate tumorigenesis. We are also investigating the role of zinc chelators as potential therapeutic agents for the treatment of castration-resistant prostate cancer. Findings from our laboratory indicate that treatment of prostate cancer cells with the zinc-chelating agent TPEN induces selective down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to cytotoxic agents.  Importantly, the observed effect is not limited to prostate cancer, as TPEN reduces expression of XIAP in malignant cell lines of various origins, including colon, ovarian, leukemia, breast and cervical cancer.  

The second major theme of our research is to determine the mechanism of tyrosine kinase inhibitor (TKIs)-resistance in genitourinary tumors. Our studies reveal that TKI-resistance coincides with the loss of phosphatase and tensin homolog (PTEN) protein expression in prostate and renal malignant cells. Conversely, expression of PTEN sensitizes prostate and renal tumors to multi-targeted tyrosine kinase inhibitor sunitinib both in vitro and in vivo. In addition, our studies indicate that an increase in expression of IL-6 and IL-8 correlates with sunitinib and pazopanib resistance in prostate and renal tumor cells.  Development of reliable biomarkers for TKI responses would be beneficial both in the clinical and in the research settings. Our recent studies are also exploring the therapeutic potential of piperine and piperlongumine, alkaloids isolated from black and long pepper, for primary and secondary prevention of urologic malignancies.  In the clinical arena, we focus our efforts on investigating the biology and natural history of small renal masses, addressing quantification of competing risks of death for patients with urologic malignancies, and improving reporting and risk-stratification of surgical outcomes for patients with kidney cancer.  

1. Golovine K, Uzzo RG, Makhov P, Crispen PL, Kunkle D, Kolenko VM. Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-κB dependent pathway. Prostate. 2008 Sep 15;68(13):1443-9. PubMed
2. Makhov P, Golovine K, Uzzo RG, Rothman J, Crispen PL, Shaw T, Scoll BJ, Kolenko VM. Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis (XIAP) and sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Cell Death and Differentiation. Cell Death Differ. 2008 Nov;15(11):1745-51. PubMed
3. Golovine K, Makhov P, Uzzo RG, Shaw T, Kunkle D, Kolenko VM. Overexpression of the zinc uptake transporter hZIP1 inhibits NF-κB and reduces the malignant potential of prostate cancer cells in vitro and in vivo. Clin Cancer Res. 2008 Sep 1;14(17):5376-84. PubMed
4. Makhov P, Golovine K, Uzzo RG, Wuestefeld T, Scoll BJ, Kolenko VM. Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells. Gene. 2009 Feb 15;431(1-2):39-46. PubMed
5. Golovine K, Makhov P, Uzzo RG, Kutikov A, Kaplan DJ, Fox E, Kolenko VM. Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-kappaB-independent, proteasome-mediated mechanism. Mol Cancer. 2010 Jul 9;9:183. PubMed