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Journal of Endocrinological Investigation

Erschienen in:

26.10.2023 | Original Article

Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay

verfasst von: E. Vitali, G. Valente, A. Panzardi, A. Laffi, A. Zerbi, S. Uccella, G. Mazziotti, A. Lania

Erschienen in: Journal of Endocrinological Investigation | Ausgabe 5/2024

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Abstract

Purpose

The finding of mTOR overactivation in patients affected by pancreatic neuroendocrine tumors (Pa-NETs) led to their treatment with the mTOR inhibitor everolimus. Unfortunately, the efficacy of everolimus is restricted by the occurrence of resistance. The mechanisms leading to Pa-NETs’ progression and resistance are not well understood. Notably, chronic inflammation is implicated in NET development. NF-kB is involved in inflammation and drug resistance mechanisms through the activation of several mediators, including STAT3. In this respect, NF-κB and STAT3 interaction is implicated in the crosstalk between inflammatory and tumor cells.

Methods

We investigated the expression of NF-kB in different Pa-NETs by RT-qPCR and immunohistochemistry. Then, we studied the role of NF-κB and STAT3 interplay in QGP-1 cells. Subsequently, we assessed the impact of NF-κB and STAT3 inhibitors in QGP-1 cell proliferation and spheroids growth. Finally, we evaluated the implication of the NF-kB pathway in everolimus-resistant Pa-NET cells.

Results

We found that the increased NF-kB expression correlates with a higher grade in Pa-NETs. The activation of the STAT3 pathway induced by TNFα is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells. Interestingly, we found that NF-kB, STAT3, IL-8, and SOCS3 are overexpressed in QGP-1R compared to QGP-1.

Conclusion

Since the NF-kB pathway is implicated in Pa-NETs’ progression and resistance to everolimus, these data could explain the potential use of NF-kB as a novel therapeutic target in Pa-NET patients.

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Titel: Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay
verfasst von: E. Vitali
G. Valente
A. Panzardi
A. Laffi
A. Zerbi
S. Uccella
G. Mazziotti
A. Lania
Publikationsdatum: 26.10.2023
Verlag: Springer International Publishing
Erschienen in: Journal of Endocrinological Investigation / Ausgabe 5/2024
Elektronische ISSN: 1720-8386
DOI: https://doi.org/10.1007/s40618-023-02221-1

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Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay

Abstract

Purpose

Methods

Results

Conclusion

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