Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.
ABSTRACT Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. RESULTS: Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. CONCLUSIONS: Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription.
Article: Changes in chromogranin a serum levels during endocrine therapy in metastatic prostate cancer patients.[show abstract] [hide abstract]
ABSTRACT: The concept of neuroendocrine (NE) differentiation in prostate cancer has become more widely recognized as its diagnostic, prognostic, and therapeutic usefulness. We enrolled 38 patients with stage D prostate cancer who underwent endocrine therapy by medical or surgical castration and oral antiandrogen. According to PSA response, serum levels of CGA as a marker of NE differentiation were measured at the multiple points of time; (1) pre-treatment, (2) complete response (CR), (3) a nadir level of PSA, (4) PSA failure or hormone independent progression. We compared these serum values in relation to efficacy of endocrine therapy. There was no correlation between serum PSA and CGA values. Patients consisted of 27 with CR and 11 without CR. Serum CGA increased as intervals of endocrine therapy became longer with positive correlation (p < 0.05). Its velocity was higher in patients with PSA failure than in those without it (6.98 vs. 2.09 ng/ml/month, p = 0.011). During endocrine therapy in metastatic prostate cancer patients, serum CGA values were not related to serum PSA levels, and increased as treatment periods became longer. It is suggested that CGA velocity has potential to predict androgen independent progression after endocrine therapy.European Urology 09/2005; 48(2):224-9; discussion 229-30. · 8.49 Impact Factor
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ABSTRACT: Recent studies suggest that NOTCH signaling can promote epithelial-mesenchymal transitions and augment signaling through AKT, an important growth and survival pathway in epithelial cells and prostate cancer in particular. Here we show that JAGGED1, a NOTCH receptor ligand, is significantly more highly expressed in metastatic prostate cancer as compared with localized prostate cancer or benign prostatic tissues, based on immunohistochemical analysis of JAGGED1 expression in human tumor samples from 154 men. Furthermore, high JAGGED1 expression in a subset of clinically localized tumors was significantly associated with recurrence, independent of other clinical parameters. These findings support a model in which dysregulation of JAGGED1 protein levels plays a role in prostate cancer progression and metastasis and suggest that JAGGED1 may be a useful marker in distinguishing indolent and aggressive prostate cancers.Cancer Research 11/2004; 64(19):6854-7. · 7.86 Impact Factor
Article: The role of somatostatin analogues in complete antiandrogen treatment in patients with prostatic carcinoma.[show abstract] [hide abstract]
ABSTRACT: Somatostatin analogues (SMS-A) have been found to inhibit the growth of experimental tumors, as of prostate cancer, via several mechanisms as antihormonal and direct antimitogenic actions. It was demonstrated also that several SMS-A induce greater prostatic tumor regression with more pronounced histological changes if combined with LHRH analogues or in association with complete androgen blockade (CAB). In a phase II clinical trial we administered, in addition to CAB, SMS-A octreotide in 14 patients with stage D2 (group B) prostate cancer-8 previously hormonally treated (PHT) and 6 without any previous hormone treatment (NPHT); 4 other patients, 3 NPHT and one PHT, were treated with CAB only (group A). Antiandrogen and antitumoral activity followed assaying a) plasma testosterone b) prostatic specific antigen (PSA) c) prostatic acid phosphatase (PAP) levels and d) objective (o) and subjective (s) clinical improvement according to WHO criteria. Somatostatin activity was evaluated assaying Insulin like Growth Factor-1 (IGF-1) and Epidermal Growth Factor (EGF). In group B we observed 3 responses, with the best quality of response (oPR/sCR) among the 6 NPHT-patients (50%) and 3 responses among the PHT-patients (37,5%), two of them with an incomplete PHT. In group A, 2 out of 3 NPHT-patients had a response (oPR/sPR). Among group B patients we observed long symptom-free survival, when they responded (17 months), in comparison to group A patients (12 months), but almost the same total duration of survival in the two groups, 18.5 and 18 months, respectively. EGF and IGF-1 serum levels showed a distinct drop parallel to the decrease of PSA serum levels, among the patients with response vs. nonrespondent patients of group B during the treatment. Although our results showed that octreotide in small doses, in addition to CAB, having mild toxicity, enhance number, quality and perhaps the duration of symptom-free responses in patients with stage 2 prostate cancer, the therapeutic efficacy of this combined treatment remains to be ascertained in wider and better randomized clinical trials.Journal of experimental & clinical cancer research: CR 04/1997; 16(1):119-26. · 1.50 Impact Factor