Prevention of pancreatic cancer in a hamster model by cAMP decrease

Abstract

Smoking and alcoholism are risk factors for the development of pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). We have previously shown that these cancers overexpressed stress neurotransmitters and cyclic adenosine monophosphate (cAMP) while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was suppressed. Using a hamster model, the current study has tested the hypothesis that cAMP decrease by GABA supplementation in the drinking water prevents the development of pancreatitis-associated PDAC. Our data reveal strong preventive effects of GABA supplementation on the development of PDAC and pancreatic intraductal neoplasia (PanIN). ELISA assays and immunohistochemistry revealed significant decreases in the levels of cAMP and interleukin 6 accompanied by reductions in the expression of several cancer stem cell markers and phosphorylated signaling proteins, which stimulate cell proliferation, and migration in pancreatic exocrine cells of GABA treated animals. We conclude that cAMP decrease by GABA supplementation inhibits multiple cancer stimulating pathways in cancer stem cells, differentiated cancer cells and the immune system, identifying this approach as promising novel tool for the prevention of PDAC in individuals with a history of smoking and alcoholism.

CD38 affects the biological behavior and energy metabolism of nasopharyngeal carcinoma cells

“…In prokaryotes, cAMP may directly activate RNA polymerase in order to promote its transcription, through the 6-factor phosphorylation level of the enzyme, to promote the transcription level of RNA. Recent studies demonstrated that the role of cAMP in eukaryotic cells was determined to be associated with regulation of transcription factors (77,78), for example, gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A. cAMP has the effect of inhibiting its cell division and promoting cell differentiation (41,42). cAMP also has a dual effect on cell proliferation, which promotes cell proliferation at early G0 or G1, and is inhibited at late G1 (42).…”

Investigation of the potential role of TGR5 in pancreatic cancer by a comprehensive molecular experiments and the liquid chromatography mass spectrometry (LC–MS) based metabolomics

“…Previous study revealed that blocking cAMP-dependent intracellular signalings may prevent the development of pancreatic cancer. It was also found that the development of pancreatic cancer was prevented by cAMP decrease in hamster models [ 37 , 38 ]. However, few studies have been reported to directly focus on the role of cAMP in migration and invasion of pancreatic cancer cells.…”

A new twist to neurotransmitter receptors and cancer

“…Preclinical studies that have employed agonists of receptors coupled to the inhibitory G-protein G i (GABA-B receptors, opioid peptide receptors) for the inhibition of β-AR-mediated progression of adenocarcinoma of the lungs and pancreas in vitro and in vivo have repeatedly shown that increases in intracellular cAMP and the associated activation of its downstream effectors are key molecular events that activate β-AR-driven development and progression of both cancers and can be successfully inhibited by agonists of G i -coupled receptors that inhibit the formation of cAMP by blocking the activation of adenylyl cyclase. [41,42,51,54,55,66,[74][75][76] A host of non-β-AR receptors coupled to the stimulatory G-protein G s increase intracellular cAMP, [3,77] a reaction not inhibited by beta-blockers but effectively counteracted by agonist-induced signaling of G icoupled receptors. There is also a host of non-betaadrenergic agents that increase intracellular cAMP directly.…”

“…[48,49] GABA is the main inhibitory neurotransmitter in the mammalian body and inhibits the AC-dependent formation of cAMP as well as the activation of voltage-gated Ca 2+channels [50] under physiological conditions by activating inhibitory G-protein (G i ) signaling downstream of G icoupled GABA-B-receptors. In light of findings that the GABA-B receptor has tumor suppressor function in pancreatic [42,[51][52][53] and non small-cell lung cancer (NSCLC) [35,41,54,55] while GABA also inhibits the in vitro growth of breast cancer and colon cancer, [47,56] suppression of GABA by psychological stress has significant tumor promoting effects on these cancers.…”