Molecular biology of prostate cancer

Karayi, M.K.; Markham, Alex F.

doi:10.1038/sj.pcan.4500697

Cited by 41 publications

(31 citation statements)

References 244 publications

(261 reference statements)

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“…In contrast, clinical studies suggest that TZDs are largely ineffective as monotherapeutic agents in treating PCa (7). Because cancer cells modify several transduction pathways to achieve continuous progression and survival (8), it is important that multiple drug-strategies are used to achieve effective treatment. Such a strategy should allow for synergistic anti-proliferative effects and/or permit the use of low drug doses that might otherwise be less effective when used as monotherapy (7).…”

Section: Introductionmentioning

confidence: 92%

Thiazolidinediones/PPARÎ³ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Haddad

2011

Int J Oncol

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Abstract. The prostate cancer (PCa) cell lines LNCaP, PC-3, and DU-145 express peroxisome proliferator-activated receptor Á (PPARÁ) but its role in PCa is unclear. Thiazolidinediones (TZDs), a family of PPARÁ activators and type 2 anti-diabetic drugs, exhibit anti-tumor apoptotic effects in human PCa cell lines. Likewise, pharmacological inhibitors of fatty acid synthase (FASN), a metabolic enzyme highly expressed in PCa, induce apoptosis in prostate and other cancer cells. Here, we show positive correlation between PPARÁ and FASN protein in PCa cell lines and synergism between TZDs and FASN blockers in PCa cell viability reduction and apoptosis induction. Combined TZDs/FASN has enhanced anti-tumor properties in both androgen-dependent LNCaP and androgen-independent PC-3 and DU-145 cells when compared with single drug exposure. Low concentrations (5-10 μM) of the TZD drug rosiglitazone failed to alter cell viability but, paradoxically, upregulated lipogenic genes [PPARÁ, FASN, sterol regulatory element binding protein-1c (SREBP-1c) and acetyl-Co A carboxylase-1 (ACC1)], which diminish the apoptotic effects of rosiglitazone. The mean IC 50 in all cell lines was 45±2 μM for rosiglitazone compared with significantly lower 5±1 μM for rosiglitazone plus the FASN blocker cerulenin, and 10.2±2 μM for rosiglitazone plus the cerulenin synthetic analog C75. The IC 50 for the combined rosiglitazone and FASN blockers contrasts with the relatively higher IC 50 for rosiglitazone (45±2 μM), the TZD drug troglitazone (13±2 μM), cerulenin (32±1 μM), or C75 (26±3 μM) when these drugs were used alone. In summary, this study shows proof-of-principle for combining FASN blockers and TZDs for PCa treatment. IntroductionProstate cancer (PCa) is second to lung cancer as a cause of cancer-related death in American men (1). Multiple preclinical studies show anti-cancer effects of thiazolidinediones (TZDs) PPARÁ agonist ligands (2-6). In contrast, clinical studies suggest that TZDs are largely ineffective as monotherapeutic agents in treating PCa (7). Because cancer cells modify several transduction pathways to achieve continuous progression and survival (8), it is important that multiple drug-strategies are used to achieve effective treatment. Such a strategy should allow for synergistic anti-proliferative effects and/or permit the use of low drug doses that might otherwise be less effective when used as monotherapy (7). For example, the antiproliferative effects of the tyrosine kinase inhibitor gefitinib in A549 lung cancer cells is enhanced with rosiglitazone as the result of rosiglitazone-induced augmentation of PTEN (phosphatase and tensin homolog) expression (9). PTEN inhibits the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway, which is essential for progression of PCa cells. Likewise, the combination of rosiglitazone and the platinum cytotoxic drugs (carboplatin and cisplatin) synergistically inhibit the growth of A549 lung cancer cells compared with single-agent therapy (10). The latter effect appears to be due to down-regulatio...

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Section: Introductionmentioning

confidence: 92%

Thiazolidinediones/PPARÎ³ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Haddad

2011

Int J Oncol

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“…3b). On the other hand, it is known that for a cancer cell to metastasize, the cells must migrate from the primary tumor and enter the circulation system [30]. Therefore, we investigated the effect of EFS overexpression on cell migration by wound-healing assay.…”

Section: Increased Expression Of Efs Repressed Malignant Behavior Of mentioning

confidence: 99%

Decreased expression of EFS is correlated with the advanced prostate cancer

et al. 2014

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Prostate cancer is the most frequently diagnosed malignant neoplasm in men in the developed countries. Although the progression of prostate cancer and the processes of invasion and metastasis by tumor cells are comparatively well understood, the genes involved in these processes are not fully determined. Therefore, a common area of research interest is the identification of novel molecules that are involved in these processes. In the present study, we have used in silico and experimental approaches to compare the expression of embryonal Fyn-associated substrate (EFS) between normal prostate and prostate cancer. We showed that EFS expression is remarkably downregulated in prostate cancer cells, compared to normal prostate cells. We also found that decreased expression of EFS in prostate cancer cells is due to DNA methylation. In addition, we showed that high EFS expression is important to suppress a malignant behavior of prostate cancer cells. Therefore, we suggest that EFS should be considered as a novel tumor suppressor gene in prostate cancer.

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“…Despite increasing efforts at early detection, 10% to 20% of the patients will show metastases at the time of diagnosis (1,2). Bone is a common site of prostate cancer metastases and bone metastases are responsible for most of the morbidity associated with this disease, such as bone pain and fractures (1,2).…”

mentioning

confidence: 99%

The Bisphosphonate Olpadronate Inhibits Skeletal Prostate Cancer Progression in a Green Fluorescent Protein Nude Mouse Model

Yang

Burton

Geller

et al. 2006

Clinical Cancer Research

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Purpose: Metastatic bone disease is one of the major causes of morbidity and mortality in prostate cancer patients. Bisphosphonates are currently used to inhibit bone resorption and reduce tumor-induced skeletal complications. More effective bisphosphonates would enhance their clinical value. Experimental Design: We tested several bisphosphonates in a green fluorescent protein (GFP)^expressing human prostate cancer nude mouse model. The in vivo effects of four bisphosphonates, including pamidronate, etidronic acid, and olpadronate, on bone tumor burden in mice intratibially inoculated with PC-3-GFP human prostate cancer cells were visualized by whole-body fluorescence imaging and X-ray. Results: The PC-3-GFP cells produced extensive bone lesions when injected into the tibia of immunocompromised mice.The skeletal progression of the PC-3-GFP cell growth was monitored by GFP fluorescence and the bone destruction was evaluated by X-ray. We showed that 3,3-dimethylaminopropane-1-hydroxy-1,1-diphosphonic acid (olpadronate) was the most effective bisphosphonate treatment in reducing tumor burden as assessed by GFP imaging and radiography. The GFP tumor area and X-ray score significantly correlated. Reduced tumor growth in the bone was accompanied by reduced serum calcium, parathyroid hormone^related protein, and osteoprotegerin. Conclusions: The serum calcium, parathyroid hormone^related protein, and osteoprotegerin levels were significantly correlated with GFP area and X-ray scores. Treatment with olpadronate reduced tumor growth in the bone measured by GFP and X-ray imaging procedures. Imaging of GFP expression enables monitoring of tumor growth in the bone and the GFP results complement the X-ray assessment of bone disease.The data in this report suggest that olpadronate has potential as an effective inhibitor of the skeletal progression of clinical prostate cancer.Prostate cancer is the most prevalent cancer in adult males.Despite increasing efforts at early detection, 10% to 20% of the patients will show metastases at the time of diagnosis (1, 2). Bone is a common site of prostate cancer metastases and bone metastases are responsible for most of the morbidity associated with this disease, such as bone pain and fractures (1, 2). The tendency of prostate cancer to spread to the skeleton indicates that tumor cells favor growth in bone. Prostate cancer cells express many factors that regulate osteoblasts and osteoclasts, including parathyroid hormone -related protein (PTHrP) and osteoprotegerin (3 -5). PTHrP was originally discovered as the causative agent that is secreted by malignancies that results in hypercalcemia. PTHrP acts as a growth regulator of many different cell types and studies by us and our colleagues have shown that PTHrP regulates prostate tumor development, growth, progression, and metastasis (4). Osteoprotegerin is a potent inhibitor of bone resorption in vivo and is expressed by prostate cancer cells. Osteoprotegerin acts as a decoy receptor, binding and inactivating the receptor activator...

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Molecular biology of prostate cancer

Cited by 41 publications

References 244 publications

Thiazolidinediones/PPARÎ³ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Thiazolidinediones/PPARÎ³ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Decreased expression of EFS is correlated with the advanced prostate cancer

The Bisphosphonate Olpadronate Inhibits Skeletal Prostate Cancer Progression in a Green Fluorescent Protein Nude Mouse Model

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