Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.

Abstract

Recent clinicopathologic studies have shown that many prostatic adenonomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal nsduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markediy neuronal morphology. Also in LNCaP cells ultrtructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest incuding S-100, chromogranin A, pp60 , and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker ppWw, and in both cell lines expression ofKS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addiion to effects on lineage markers, cAMP treatment induced GI synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plastic in the lineag commitment of adenocarcinoma of the prostate. We have shown that cellpermeant cAMP analogue can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.In an effort to develop new anticancer drugs directed at unique aspects of prostate cancer biology, we have been studying the signal transduction pathways regulating the growth of human prostate adenocarcinoma cells in vitro. As reported previously, we found that addition of dibutyryl (db) cAMP to the androgen-independent prostate carcinoma cell line PC-3 causes induction of type (32 transforming growth factor (TGF-g32) mRNA, production of bioactive TGF-P2, and growth arrest (1).We have subsequently studied the effect of cAMP derivatives and phosphodiesterase inhibitors on the other two commonly available prostate carcinoma cell lines, DU 145 and LNCaP, as well as the highly metastatic variant of PC-3, PC-3-M, and found that all lines were growth inhibited by elevation of intracellular cAMP (data not shown). Data presented here demonstrate that in two ofthese lines, LNCaP and PC-3-M, elevation of intracellular cAMP induces permanent conversion from an epithelial to a neuronal morphology and that these cells express markers of the neuroendocrine phenotype. These data suggest that these cell lines, which are derived from metastatic adenocarcinoma of the prostate, contain or consist of multipotent cells capable of both neuroendocrine and epithelial differentiation.

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

“…Activation of the PKA pathway by FSK or other compounds can increase proliferation, alter cell morphology, and induce neuroendocrine differentiation of prostate cancer cells (Bang et al, 1994;Shah et al, 1994;Chen et al, 1999;Cox et al, 2000;Farini et al, 2003).…”

“…The cAMP-PKA pathway is tightly regulated at several levels and itself is involved in the regulation of diverse cellular processes such as cell cycle, proliferation and differentiation and regulation of microtubule dynamics, chromatin condensation and decondensation, nuclear envelope disassembly and reassembly, as well as regulation of intracellular transport mechanisms and ion fluxes (Tasken and Aandahl, 2004). Neuroendocrine differentiation of prostate cancer cells is implicated in androgen-independent prostate cancer and can be induced in LNCaP cells by activation of the PKA pathway (Bang et al, 1994;Cox et al, 2000). Cross-talk between the AR and PKA signal transduction pathways occurs in androgen-depleted human prostate cancer cells maintained in culture .…”

Epac inhibits migration and proliferation of human prostate carcinoma cells

“…In fact, elevated levels of the subfamily of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) could be observed in advanced prostate tumours (Gioeli et al, 1999;Price et al, 1999;Uzgare et al, 2003). In prostate carcinoma cells, cAMP analogues, such as Bt2-cAMP or dbcAMP, not only inhibited proliferation and migration but also induced cell differentiation (Bang et al, 1992(Bang et al, , 1994Picascia et al, 2002;Chen et al, 2005), thereby presenting potential new therapeutical treatment options.…”

In Vitro Differentiation of Canine Celiac Adipose Tissue-Derived Stromal Cells into Neuronal Cells

“…Differentiated human BMSCs also show NSE expression by the same treatment in vitro [4,15]. The treatment with dbcAMP and IBMX, both of which elevate intracellular cAMP level, induces terminal neuroendocrine dfferentiation in prostate tumor cells and C6 glioma cells [2,3,8,16]. Therefore, an increase of intracellular cAMP is a trigger of differentiation into early neural cells for ATSCs like as reported for BMSCs [4].…”