The loss of tumor-and/or metastasis-suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor-suppressor and metastasis-suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75 NTR . The p75 NTR is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75 NTR expression with the malignant progression of the prostate, consistent with a pathologic role of the p75 NTR as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU-pr1 and PC-3 human prostate tumor cell lines that exhibit a rank order (dose-dependent) increase in p75 NTR protein expression, we investigated the effects of the p75 NTR in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose-dependent) increase in p75 NTR expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose-dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75 NTR . This suggests that p75 NTR is a tumor suppressor of growth and a metastasis suppressor of NGF-stimulated migration of human prostate tumor cells.
NTR is an important upstream modulator of the anticancer effects of NSAIDs and that ibuprofen induction of the p75 NTR protein establishes an alternate mechanism by which ibuprofen may exert an anticancer effect.
Epididymal epithelial cells isolated from mature rats and Sertoli cells isolated from 10-day-old rats were cultured in serum-free defined media on extracellular matrix impregnated filters maintained in dual environment culture chambers. Epididymal epithelial cells had a polarized appearance only when plated at high density (greater than 1 X 10(6) cells/cm2). Confluent monolayers of these cells formed a permeability barrier to inulin. Sertoli cells were columnar and highly polarized when grown on extracellular matrix-impregnated filters, cuboidal when grown on filters alone, and squamous when grown on plastic. Confluent polarized monolayers of these cells excluded the electron-dense tracer lanthanum nitrate by way of basal-tight junctions. Therefore, polarized monolayers of epididymal epithelial cells and Sertoli cells can be obtained by growing the cells at high density on extracellular matrix-impregnated permeable supports. By maintaining the monolayers in specially constructed culture chambers, the cells can develop a permeability barrier, and are able to achieve the separation of apical from basal compartments so important for their function in vivo.
Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75 NTR protein.
p75NTR has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75 NTR and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75 NTR relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75 NTR protein levels, the expression of Fas, p55 TNFR , DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before Rflurbiprofen or ibuprofen treatment with a dominant negative form of p75 NTR to antagonize p75 NTR activity or p75 NTR small interfering RNA to prevent p75 NTR protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75 NTR -dependent decreased survival of prostate cancer cells independently of COX inhibition. [Cancer Res 2007;67(7):3254-62]
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