Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status

Abstract

SummaryRegulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH.

Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy

“…In prostate cancer tissues, there is simultaneously an increased expression of choline acetyltransferase, the enzyme catalyzing the synthesis and secretion of acetylcholine, and M3 muscarinic receptors (CHRM3) (221). Experimentally, activation of acetylcholine receptors increases prostate cancer proliferation and migration (222). In addition to prostate cancer, muscarinic receptors have also been implicated in SCLC and CRC stimulating cancer cell growth with acetylcholine as an autocrine growth factor (223,224).…”

Salt Gradient Modulation of MicroRNA Translocation through a Biological Nanopore

“…[4][5][6] Instead, Wanunu et al and Wang et al established that specific miRNAs in a total RNA extract can be quantified by simply counting the number of molecules that traverse a nanopore. 7,8 Each translocation event is manifested as a transient current decrease because poreconfined miRNA displaces electrolyte ions. 9,10 This application of nanopore resistive pulse sensing requires an oligonucleotide probe selective for the miRNA species of interest, with assay sensitivity determined by the rate at which the miRNA−probe duplex is captured by the pore.…”

“…7,12,14 For the biological nanopore a-hemolysin (aHL), a duplex blocks the pore entrance because the channel constriction is ~1.4 nm, whereas a non-hybridized oligonucleotide rapidly (~0.1 ms) translocates the pore. 8,12,15 After ~100−1000 ms the duplex dissociates in the aHL vestibule, with subsequent rapid pore translocation of the DNA and miRNA. 8,16 In order to accurately relate the stochastic current block events with analyte concentrations, ~200 translocation events need to be analyzed 7,17 in a time frame, imposed by assay throughput and pore stability considerations, of ~30 mins, implying a minimum event frequency of ~5 translocations per minute (~0.1 events s -1 ).…”

Potentiometric sensing of nucleic acids using chemically modified nanopores

“…0.1 nM and 1 nM) 20,60,61 but lags behind methods using salt gradient amplification. 62 However, we believe that the simple detection methodology that this potentiometric sensing concept offers is very appealing compared to the complexity of resistive pulse sensing, which generally requires pores of less than 5 nm in diameter for direct detection of NAs. The optimization of the nanopore geometry and modification along the directions determined in this study may further improve the analytical performance.…”