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Modulation of pancreatic neuroendocrine neoplastic cell fate by autophagy mediated death.

Abstract：

:Introduction Autophagic cell death in cancer cells can be mediated by inhibition of deacetylases. Although extensive studies have focused on the autophagic process in cancer, little is known about the role of autophagy in degrading cytosolic and nuclear components of pancreatic neuroendocrine neoplastic (pNEN) cells leading to cell death, thus improving the therapy of patients affected by pNEN. Methods 2D and 3D human pNEN and pancreatic stellate cells were treated with panobinostat and bafilomycin. Autophagy markers were detected by RT-qPCR, immunofluorescence and western blot. Autophagosomes were detected by electron microscopy and their maturation by real time fluorescence of LC3B stable transfected cells. ChIP was performed at the cAMP responsive element. Immunofluorescence was performed in murine pancreatic tissue. Results We observed that pan-deacetylase inhibitor panobinostat treatment causes autophagic cell death in pNEN cells. We also found that although AMPK-α phosphorylation is counterbalanced by phosphorylated AKT, it is not capable to inhibiting autophagic cell death. Whereas the binding activity of cAMP responsive element is prompted by panobinostat. Although autophagy inhibition prevented autophagosomes synthesis, maturation and cell death, panobinostat treatment induced the accumulation of mature autophagosomes in the cytosol, and the nucleus, leading to disruption of the organelles, cellular digestion and decay. Observation of autophagosome membrane proteins Beclin1 and LC3B aggregation in murine pancreatic islets indicates that autophagy restoration may also lead to autophagosome aggregation in murine insulinoma cells. A basal low expression of autophagy markers was detectable in patients affected by pNEN and, interestingly, the expression of these markers was significantly lower in metastatic pNEN. Discussion/Conclusion Our study highlights that the autophagy functional restoration and prolongation of this catabolic process, mediated by inhibition of deacetylase, is responsible for the reduction of pNEN cells. Prompting of autophagy cell death could be a promising strategy for the therapy of pNEN.

journal_name

Neuroendocrinology

journal_title

Neuroendocrinology

authors

Matrood S,de Prisco N,Wissniowski T,Wiese D,Jabari S,Griesmann H,Wanzel M,Stiewe T,Neureiter D,Klieser E,Mintziras I,Buchholz M,Bartsch DK,Gennarino V,Di Fazio P

doi

10.1159/000512567

subject

Has Abstract

pub_date

2020-10-27 00:00:00

eissn

0028-3835

issn

1423-0194

pii

000512567

pub_type

杂志文章

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Modulation of pancreatic neuroendocrine neoplastic cell fate by autophagy mediated death.