Androgen-Independent Growth and Tumorigenesis of Prostate Cancer Cells Are Enhanced by the Presence of PKA-Differentiated Neuroendocrine Cells

Abstract

The neuroendocrine status of prostatic adenocarcinomas is considered a prognostic indicator for development of aggressive, androgen-independent disease. Neuroendocrine-like cells are thought to function by providing growth and survival signals to surrounding tumor cells, particularly following androgen ablation therapy. To test this hypothesis directly, LNCaP cells were engineered to inducibly express a constitutively activated form of the cyclic AMP-dependent protein kinase A catalytic subunit (caPKA), which was previously found upon transient transfection to be sufficient for acquisition of neuroendocrine-like characteristics and loss of mitotic activity. Clonal cells that inducibly expressed caPKA enhanced the growth of prostate tumor cells in anchoragedependent and anchorage-independent in vitro assays as well as the growth of prostate tumor xenografts in vivo, with the greatest effects seen under conditions of androgen deprivation. These results suggest that neuroendocrine-like cells of prostatic tumors have the potential to enhance androgenindependent tumor growth in a paracrine manner, thereby contributing to progression of the disease. [Cancer Res 2007;67(8):3663-72]

Overexpressing PKIB in prostate cancer promotes its aggressiveness by linking between PKA and Akt pathways

“…Coupling with G-proteins, it activates a number of ligand-receptor signaling pathways and controls cell growth and differentiation (Stork and Schmitt, 2002;Tasken and Aandahl, 2004). In PC, several reports have suggested its involvement with androgen-independent growth and neuroendocrine differentiation (Cox et al, 2000;Deeble et al, 2007), as well as with the cross-talk between the PKA and AR pathways in PCs (Sadar, 1999;Stork and Schmitt, 2002). The PKA pathway is regulated by many factors, including PKA-regulatory subunits (PKA-Rs) and endogenous PKA inhibitors (Miller, 2002;Taylor et al, 2005).…”

Neuroendocrine differentiation in prostate cancer

“…Experimental evidence has been presented showing that NE tumor cells can promote androgen-independent growth and tumorigenesis, 6 and invasion and metastasis of prostate cancer cells, 7 likely through their secreted products. 8,9 Studies over the years have shown that NE cells secret biogenic amines, neuropeptides and cytokines, while the bulk, non-NE tumor cells express receptors for many of the NE cell products.…”

A Prominent Couple

“…It was further shown that NE cancer cells secrete growth stimulating peptides (e.g. bombesin) inducing increased proliferation of adjacent PCa cells [86,[88][89][90][91][92][93]. However, in small cell PCa cells, upregulation of mitotic genes (UBE2C, AURKA) and the proliferation-associated polo-like kinase 1 (PLK1) co-expressed with NE markers was identified [86] [94,95].…”

“…By identifying an additive effect of SRRM4 and AR pathway inhibition to induce NEPC, the researchers proposed a role for ADT as prerequisite condition to release a lineage-specific differentiation program and preparing transformation to NEPC [89]. The placental gene PEG10 was identified as driver of NEPC in a dynamic progression xenograft model revealing a biphasic expression pattern during distinct stages of NEPC development [90]. PEG10 expression increased during enzalutamide-mediated AR inhibition in the initial progression phase.…”

“…PEG10 expression increased during enzalutamide-mediated AR inhibition in the initial progression phase. A second increase was detected at the emergence of NEPC promoting cell cycle progression in the context of RB1 and TP53 loss, and triggering invasion by increased SNAIL expression via TGF-β signaling [90]. It was initially assumed that NEPC developed from outgrowth of normal prostatic NE cells, promoted by the selective pressure of androgen-independent growth [91].…”