title: The Roles of PI3K/AKT/mTOR and MAPK/ERK Signaling Pathways in Human Pheochromocytomas.
abstract: Objectives. The roles of PI3K/AKT/mTOR and MAPK/ERK pathways involved in the pathogenesis of pheochromocytoma and paraganglioma (PPGL) were demonstrated mostly byin vitrostudies with rat or mouse cells and were mainly studied at transcriptional level. This study aimed to investigate the effect of these pathways on the proliferation of human PPGL cells and the activation of these pathways in PPGLs.Methods. Human PPGL cells were treated with sunitinib and inhibitors of PI3K (LY294002), MEK1/2 (U0126), and mTORC1/2 (AZD8055). Cell proliferation was detected by MTT assay. Protein phosphorylation was detected by Western blotting.Results. In most PPGLs, AKT, ERK1/2, and mTOR were activated. LY294002 (10μM), U0126 (10μM), AZD8055 (1μM), and sunitinib (1μM) inhibited PPGL cell proliferation in ten primary cultures of tissues, including four from patients with gene mutations. MEK1/2 inhibitor decreased mTOR phosphorylation. Inhibition of mTOR reduced phosphorylation of AKT and ERK1/2. Sunitinib inhibited phospho-ERK1/2 and phospho-mTOR.Conclusion. Our study suggested that PI3K/AKT/mTOR and MAPK/ERK signaling pathways play vital roles in human PPGL and are activated in most PPGLs. Inhibiting multiple pathways might be a novel therapeutic approach for PPGLs.
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China.
authors.forename: Juan
authors.identifier: 0000-0002-0271-1709
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China.
authors.forename: Anli
authors.identifier: 0000-0002-5432-5818
authors.initials: A
authors.lastname: Tong
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China.
authors.forename: Yunying
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China.
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Yan