Activated mTOR signaling promotes the expression of PGC1α and mortalin in pancreatic neuroendocrine tumours
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Abstract
Pancreatic neuroendocrine tumors (panNETs) are a rare malignancy that is difficult
to treat. Since a considerable number of panNETs exhibit high mTOR pathway
activity, current therapeutic strategies for advanced panNETs often involve the use
of mTOR inhibitors. Recently, there has been discussion regarding the potential
benefits of combining mTOR inhibition with therapies targeting cellular metabolism.
These are based on observations that mTOR signalling also impacts mitochondrial
functions and the expression of nuclear-encoded mitochondria-related genes.
However, the precise interaction between mTOR and mitochondrial function,
particularly in the context of panNETs, remains poorly understood. Consequently,
the objective of this study is to identify proteins that connect these two systems and
assess the functional implications of this relationship.
In the present study, a well-characterized cohort of 157 panNETs was established.
We identified pS6 as a reliable biomarker for the mTOR pathway activity in panNET,
as we revealed that 22 % of the investigated panNET exhibit mTOR pathway activity
by expression analysis of pS6. We could verify this finding by identifying the
mTORc1 pathway as the most upregulated pathway in panNET with activated mTOR
pathway using RNA-sequencing and gene set enrichment analysis (GSEA). In
addition, we were able to identify two mitochondria related proteins as targets of
mTOR in panNET. RNA sequencing of panNET tissue and cell lines highlighted
PGC1α as the most significantly upregulated gene in tumors with activated mTOR
and in the BON1 cell line control group that was compared to BON1 cells treated
with mTOR inhibitors. Furthermore, mortalin was found to be highly upregulated in
high-grade panNETs with elevated mTOR activity. Interestingly, PGC1α was shown
to influence mTOR pathway activity, while mortalin did not impact mTOR signaling.
We could not find any correlation between somatic mutations in the mitochondrial
DNA and the mTOR pathway activity
In summary, these findings offer valuable insights into the molecular interactions
between mTOR signalling and the mitochondria-related proteins mortalin and
PGC1α in panNETs. This may pave the way for new treatment options for this rare
tumor entity, offering benefits for patients.