PMID- 36604142 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230211 IS - 1745-7270 (Electronic) IS - 1672-9145 (Print) IS - 1672-9145 (Linking) VI - 54 IP - 11 DP - 2022 Nov 25 TI - MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors. PG - 1599-1609 LID - 10.3724/abbs.2022162 [doi] AB - Pancreatic neuroendocrine tumor (pNET) is the second most common malignant tumors of the pancreas. Multiple endocrine neoplasia 1 ( MEN1) is the most frequently mutated gene in pNETs and MEN1-encoded protein, menin, is a scaffold protein that interacts with transcription factors and chromatin-modifying proteins to regulate various signaling pathways. However, the role of MEN1 in lipid metabolism has not been studied in pNETs. In this study, we perform targeted metabolomics analysis and find that MEN1 promotes the generation and oxidation of polyunsaturated fat acids (PUFAs). Meanwhile lipid peroxidation is a hallmark of ferroptosis, and we confirm that MEN1 promotes ferroptosis by inhibiting the activation of mTOR signaling which is the central hub of metabolism. We show that stearoyl-coA desaturase (SCD1) is the downstream of MEN1-mTOR signaling and oleic acid (OA), a metabolite of SCD1, recues the lipid peroxidation caused by MEN1 overexpression. The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, we find that BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pNETs that targets mTOR signaling. In addition, combined use everolimus with ferroptosis inducer, RSL3, possesses a more powerful ability to kill cells, which may provide a new strategy for the comprehensive therapy of pNETs. FAU - Ye, Zeng AU - Ye Z AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Chen, Haidi AU - Chen H AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Ji, Shunrong AU - Ji S AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Hu, Yuheng AU - Hu Y AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Lou, Xin AU - Lou X AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Zhang, Wuhu AU - Zhang W AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Jing, Desheng AU - Jing D AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Fan, Guixiong AU - Fan G AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Zhang, Yue AU - Zhang Y AD - Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China. FAU - Chen, Xuemin AU - Chen X AD - Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China. FAU - Zhuo, Qifeng AU - Zhuo Q AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Chen, Jie AU - Chen J AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Xu, Xiaowu AU - Xu X AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Yu, Xianjun AU - Yu X AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Xu, Jin AU - Xu J AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Qin, Yi AU - Qin Y AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. FAU - Gao, Heli AU - Gao H AD - Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. AD - Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. AD - Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. LA - eng PT - Journal Article PL - China TA - Acta Biochim Biophys Sin (Shanghai) JT - Acta biochimica et biophysica Sinica JID - 101206716 RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 1.14.19.1 (SCD1 protein, human) RN - EC 1.14.19.1 (Stearoyl-CoA Desaturase) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Transcription Factors) RN - 0 (MEN1 protein, human) RN - 0 (Proto-Oncogene Proteins) SB - IM MH - Humans MH - Everolimus MH - *Ferroptosis MH - *Neuroendocrine Tumors/genetics/pathology MH - *Pancreatic Neoplasms/genetics/pathology MH - Stearoyl-CoA Desaturase/genetics MH - TOR Serine-Threonine Kinases MH - Transcription Factors MH - *Proto-Oncogene Proteins/genetics PMC - PMC9828289 OTO - NOTNLM OT - MEN1 OT - SCD1 OT - ferroptosis OT - mTOR signaling OT - pancreatic neuroendocrine tumor COIS- The authors declare that they have no conflict of interest. EDAT- 2023/01/06 06:00 MHDA- 2023/01/10 06:00 PMCR- 2022/11/08 CRDT- 2023/01/05 21:13 PHST- 2023/01/05 21:13 [entrez] PHST- 2023/01/06 06:00 [pubmed] PHST- 2023/01/10 06:00 [medline] PHST- 2022/11/08 00:00 [pmc-release] AID - 10.3724/abbs.2022162 [doi] PST - ppublish SO - Acta Biochim Biophys Sin (Shanghai). 2022 Nov 25;54(11):1599-1609. doi: 10.3724/abbs.2022162.