AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy.
Samantha ExnerClaudia SchuldtSachindra SachindraJing DuIsabelle Heing-BeckerKai LichaBertram WiedenmannCarsten GrötzingerPublished in: Cancers (2020)
This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal (n = 71) NEN tissues compared to controls (n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.
Keyphrases
- induced apoptosis
- angiotensin ii
- pet imaging
- cell cycle arrest
- poor prognosis
- mouse model
- binding protein
- signaling pathway
- gene expression
- cell death
- stem cells
- high resolution
- endoplasmic reticulum stress
- living cells
- small molecule
- quantum dots
- computed tomography
- cell proliferation
- oxidative stress
- vascular smooth muscle cells
- long non coding rna
- mass spectrometry
- fluorescence imaging
- transcription factor
- photodynamic therapy
- cell therapy