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?2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

ABSTRACT: Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective ?-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.

SUBMITTER: Renz BW

PROVIDER: S-EPMC5760435 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

Renz Bernhard W BW Takahashi Ryota R Tanaka Takayuki T Macchini Marina M Hayakawa Yoku Y Dantes Zahra Z Maurer H Carlo HC Chen Xiaowei X Jiang Zhengyu Z Westphalen C Benedikt CB Ilmer Matthias M Valenti Giovanni G Mohanta Sarajo K SK Habenicht Andreas J R AJR Middelhoff Moritz M Chu Timothy T Nagar Karan K Tailor Yagnesh Y Casadei Riccardo R Di Marco Mariacristina M Kleespies Axel A Friedman Richard A RA Remotti Helen H Reichert Maximilian M Worthley Daniel L DL Neumann Jens J Werner Jens J Iuga Alina C AC Olive Kenneth P KP Wang Timothy C TC

Cancer cell 20171214 1

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras<sup>+/G12D</sup>;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival ...[more]

PMID: 29249692

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Project description:BackgroundThis study investigates the allosteric coupling that exists between the intra- and extracellular parts of human β2-adrenergic receptor (β2-AR), in the presence of the intracellular loop 3 (ICL3), which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 μs long MD run has revealed a transition to the so-called very inactive state of the receptor, in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously, an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study, we performed independent runs with a total duration of 4 μs to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site).ResultsIn all three independent unrestrained runs (each 500 ns long), ICL3 preserved its initially packed/closed conformation within the studied time frame, suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site, which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure, whereas a relatively constrained/closed binding site hindered ICL3 packing. However, the reverse operation, i.e. opening of the packed ICL3, could not be realized by restraining the binding site region to a closed state. Thus, any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds.ConclusionsOverall, our simulations indicated that starting with very inactive states, the receptor stayed almost irreversibly inhibited, which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site, induced the expected conformational changes in TM5, TM6 and consequently, ICL3. Still, once ICL3 was packed, the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.

Dataset Information

?2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

Publications

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

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