title: Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma.
abstract: Recent studies have found that mammalian target of rapamycin complex 2 (mTORC2) is emerging as a potential therapeutic target in the treatment of many human cancers. However, the effects of targeting of mTORC2 on malignant pheochromocytomas (PCC) and paragangliomas (PGL) have not been reported. The aim of the study was to investigate the effects of targeting of mTORC2 on malignant PCC/PGL by comparing the inhibitory effects of targeting of mTORC2 with mTORC1 on pheochromocytoma PC12 cell in vitro and vivo. The expressions of regulatory-associated protein of mTOR (raptor) and rapamycin-insensitive companion of mTOR (rictor) were detected by immunohistochemistry in human tissues of malignant PCC. Targeting of mTORC1, mTORC2, and mTORC1/2 (mTORC1 and mTORC2) were performed by transfected with raptor, rictor, and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) in pheochromocytoma PC12 cell, respectively. MTT assay, apoptosis analysis, wound healing, and Transwell approach were performed. A tumor model in nude mice bearing PC12 cell xenografts, which were dosed with rapamycin or PP242, was established. The expression of raptor was frequently moderate positive, but the expression of rictor was frequently strong positive in malignant PCC. In vitro, although inhibition of mTORC1 was able to suppress PC12 cell proliferation, inhibition of mTORC2 more effectively suppressed cell proliferation. Inhibition of mTORC2 or mTORC1/2 more effectively prevented cell migration and invasion, and promoted cell apoptosis, while inhibition of mTORC1 only slightly prevented cell migration and invasion, and was not able to promoted apoptosis. Also, we found that mTOR downstream kinases were deregulated by targeting of mTORC2, but not mTORC1. In vivo, we found that PP242 was more potent than rapamycin in inhibiting tumor growth in tumor model. Our data suggest that targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant PCC/PGL. However, more clinical trials are needed to prove our findings.
authors: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
authors: Xiaohua
authors: X
authors: Zhang
authors: Xianjin
authors: X
authors: Wang
authors: Tianyuan
authors: T
authors: Xu
authors: Shan
authors: S
authors: Zhong
authors: Zhoujun
authors: Z
authors: Shen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000187:drug effects / Q000235:genetics*; D010235:Paraganglioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010673:Pheochromocytoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011687:Purines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007211:Indoles; D046912:Multiprotein Complexes; D011687:Purines; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus