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The laboratory's main focus is in three different disease areas that affect many urologic patients.
Aria F. Olumi, M.D. (PI) Rongbin Ge, M.D., PhD. Jijun Li (PhD candidate) Zongwei Wang, M.D. PhD. Gregory Wirth, M.D. Xingyuan Xiao (PhD candidate)
1. Molecular Mechanisms of Resistance to Pro-Apoptotic Agents
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) delivers potent antitumor pro-apoptotic activity, and cancer cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Therefore TRAIL is an ideal cancer therapeutic agent without significant side effects. However, some cancer cells develop resistance to TRAIL induced apoptosis. To overcome resistant cancer cells, it’s important to identify molecular pathways that differentiate between sensitive and resistant cancers. Recently, we found that the transcription factor FBXL10 has an anti−apoptotic role and mediates sensitivity to TRAIL-mediated apoptosis. We demonstrate a novel NF-kB/FBXL10/c-Fos/c-FLIP signaling pathway in TRAIL−mediated apoptosis. Our studies suggest that inhibiting FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. Identifying molecular pathways that differentiate between TRAIL-resistant and sensitive cancer cells will improve our currently available pro-apoptotic medications and will lead to development of new and more effective pro-apoptotic agents.
2. Molecular Mechanisms of Bladder Dysfunction Associated with Type 2 Diabetes
Diabetes mellitus (DM) affects 7% of the US population. Annually, one and a half million new cases of diabetes are diagnosed. The annual estimated cost of health care related to diabetes exceeds $130 billion dollars, with $90 billion for direct medical cost and $40 billion for indirect costs such as disability, work loss and premature mortality. While DM-type 1 is thought to be secondary to autoimmune destruction of pancreatic beta cells that produce insulin, the more common type of diabetes mellitus type 2 (DM2), stems from insulin resistance. DM2 accounts for 90% of newly diagnosed cases in the US, and it is associated with a chronic hyperglycemic environment which can have deleterious complications of heart disease, stroke, hypertension, retinopathy, neuropathy, nephropathy and complications during pregnancy. From a urologic standpoint, patients present with voiding complaints, recurrent urinary tract infections and erectile dysfunction. Diabetic bladder dysfunction is a common complication and affects up to 80% of patients with diabetes, and patients present with decreased bladder sensation, increased residual urine volume, and bladder overactivity. Often, patients present with late stages of bladder dysfunction, which include inability to urinate secondary to poorly functioning decompensated bladder smooth muscle. Identifying molecular changes that are responsible for diabetic bladder dysfunction may help identify diabetic patients at risk of developing bladder dysfunction prior to presentation of the late stages of the disease. Collaborating with investigators in Children’s Hospital Boston, we identified a genetic mouse model with DM2 with conditional hepatocyte double knockout of insulin receptor substrates 1 & 2 (DKO), which mimic the diabetic bladder dysfunction in humans. DKO mice exhibited abnormal spontaneous bladder contractions, with higher amplitudes of tension to different stimulation at young ages (6, 12 weeks), while older mice demonstrated lower amplitudes – findings which are common in patients with diabetic bladder dysfunction.
To understand the molecular alterations associated with diabetic bladder dysfunction we used differential gene expression profiling, and found that the TNF superfamily inflammatory genes were up-regulated. Inhibition of the TNF pathways in in-vivo and in-vitro assays correct the bladder dysfunction that is associated with diabetic bladder cystopathy.
Our findings demonstrate that diabetic cystopathy in DKO mice is a progressive process – hyperactive bladder dysfunction in early/middle aged animals and hypoactive in older animals. Systemic inhibition of the TNF pathway in diabetic mice corrected the diabetic cystopathy without affecting serum glucose levels, suggesting that hyperglycemia alone may not be responsible for secondary complications of diabetes. Evaluating the molecular pathways that lead to diabetic cystopathy will improve our understanding of bladder dysfunction, and help devise preventive strategies for secondary complications associated with type 2 diabetes.
3. 5-alpha reductase 2 (5-AR2) is a key enzyme that is responsible of proper development of prostate tissue.
Inhibition of 5-AR2 has proven to be efficacious for management of urinary symptoms secondary benign prostatic hyperplasia (BPH). However, some patients are resistant to the therapeutic effects of 5-AR2 inhibitor for management lower urinary tract symptoms. We show that 30% of benign human prostate samples did not express the 5-AR 2 protein. Moreover, we demonstrate that the promoter region of 5-AR 2 contains a CpG island that is methylated in benign prostate epithelial cells in culture and also in 39% of benign human prostate samples. We conclude that methylation of 5-AR 2 promoter may account for low or absent expression of 5-AR 2 in human adult prostate tissues. Low or absent levels of 5-AR 2 in human prostate may have implications in long term prostatic growth rate and treatment strategies for management of BPH.
1. Zhang X, Zhang L, Yang H, Huang, X, Otu H, Liberman T, DeWolf WC, Khosravi-Far R, Olumi AF. c-Fos as a pro-apoptotic agent in TRAIL-induced apoptosis in prostate cancer cells. Cancer Research. 2007;67:9425-34.
2. Li W, Zhang X, Olumi AF. MG-132 Sensitizes TRAIL-resistant Prostate Cancer Cells by Activating c-Fos/c-Jun Heterodimers and Repressing c-FLIP(L). Cancer Research. 2007;67(5):2247-55.
3. Li W, Wu CH, Febbo PG, Olumi AF. Stromally expressed c-Jun regulates proliferation of prostate epithelial cells. American Journal of Pathology. 2007;171:1189-98.
4. Olumi AF, DeWolf WC. The Hybrid of Basic Science and Clinical Training for the Urologic Oncologist: Necessity or Waste? Urologic Oncology. 2009;27:205-7.
5. Zhang X*, Huang X*, Olumi AF (*contributed equally). Repression of NF-kB and Activation of AP-1 Enhance Apoptosis in Prostate Cancer Cells. International Journal of Cancer. 2009;124(8):1980-9.
6. Ge R, Wang Z, Zeng Q, Xu X, Olumi AF. F-box protein 10: a novel NF-κB-dependent anti-apoptotic protein regulates TRAIL-induced apoptosis. 2010; (Submitted)
7. Niu N, Hu L, Diaz C, Ge R, Wang Z, Wu CL, Olumi AF. Reduced Levels of 5-α Reductase 2 in Adult Prostate Tissue and Implications for BPH Therapy. 2010; (Submitted)
8. Wang Z, Ge R, Olumi AF, Apoptosis in Prostate Cancer. In: Apoptosis. Preedy, V, editor. Science Publishers (in press).
Aria F. Olumi, MD
Yawkey Building 7E
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