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Oncotarget. 2017 Mar 28;8(13):20974-20987. doi: 10.18632/oncotarget.15469.

mTOR inhibitors activate PERK signaling and favor viability of gastrointestinal neuroendocrine cell lines.

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University Lyon, Claude Bernard University, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Faculty of Pharmacy, F-69008, Lyon, France.
Hospices Civils de Lyon, Molecular Biology of Tumors, GHE Hospital, F-69500, Bron, France.
Hospices Civils de Lyon, Digestive Oncology, Hospital E Herriot, F-69432, Lyon, France.
Institut Gustave Roussy, Biopathology, F-94800 Villejuif, France.
University Paris Sud, F-91400 Orsay, France.


mTOR and Unfolded Protein Response (UPR) are two signaling pathways frequently activated in cancer cells. The mTOR pathway has been shown to be up-regulated in most gastroenteropancreatic neuroendocrine tumors. In contrast, little is known about the UPR status in neoplastic neuroendocrine cells. However, these hormone-producing cells are likely to present distinctive adaptations of this pathway, as other secretory cells. We therefore analyzed the status of the three axes of UPR and their relation to mTOR pathway in two gastrointestinal neuroendocrine tumors (GI-NET) cell lines STC-1 and GluTag. At baseline, pharmacological inducers activate the three arms of UPR: PERK, ATF6 and IRE1. Although hypoxia stimulates the PERK, ATF6 and IRE-1 pathways in both cell lines, glucose depletion activates UPR only in STC-1 cell line. Strikingly, P-p70S6K1 increases concomitantly to P-PERK and BiP in response to thapsigargin treatment, glucose depletion or hypoxia. We found that different mTOR inhibitors activate the PERK signaling pathway. To confirm that mTOR inhibition modulates PERK activation, we inhibited PERK and showed that it decreased cell viability when associated to mTOR inhibition, indicating that mTOR drives a PERK-dependent survival pathway. In conclusion, in GI-NET cell lines, UPR signaling is functional and PERK arm is induced by mTOR inhibition. These observations open up new perspectives for therapeutic strategies: the crosstalk between mTOR and UPR might contribute to the resistance to mTOR inhibitors and could be targeted by mTOR and PERK inhibitors in combination therapy.


GI-NET; PERK; UPR; mTOR; neuroendocrine cell lines

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