PMID- 25666752
OWN - NLM
STAT- MEDLINE
DCOM- 20151026
LR  - 20211203
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 36
IP  - 7
DP  - 2015 Jul
TI  - Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the 
      treatment of malignant pheochromocytoma.
PG  - 5273-81
LID - 10.1007/s13277-015-3187-7 [doi]
AB  - 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.
FAU - Zhang, Xiaohua
AU  - Zhang X
AD  - Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of 
      Medicine, Shanghai, 200025, China.
FAU - Wang, Xianjin
AU  - Wang X
FAU - Xu, Tianyuan
AU  - Xu T
FAU - Zhong, Shan
AU  - Zhong S
FAU - Shen, Zhoujun
AU  - Shen Z
LA  - eng
PT  - Journal Article
DEP - 20150211
PL  - Netherlands
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental 
      Biology and Medicine
JID - 8409922
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Indoles)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Purines)
RN  - 0 (RICTOR protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/biosynthesis/genetics
MH  - Adrenal Gland Neoplasms/drug therapy/*genetics/pathology
MH  - Animals
MH  - Carrier Proteins/biosynthesis/genetics
MH  - Humans
MH  - Indoles/administration & dosage
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Multiprotein Complexes/drug effects/*genetics
MH  - Paraganglioma/drug therapy/*genetics/pathology
MH  - Pheochromocytoma/drug therapy/*genetics/pathology
MH  - Purines/administration & dosage
MH  - RNA, Small Interfering/genetics
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Sirolimus/administration & dosage
MH  - TOR Serine-Threonine Kinases/biosynthesis/drug effects/*genetics
MH  - Xenograft Model Antitumor Assays
EDAT- 2015/02/11 06:00
MHDA- 2015/10/27 06:00
CRDT- 2015/02/11 06:00
PHST- 2014/11/08 00:00 [received]
PHST- 2015/01/30 00:00 [accepted]
PHST- 2015/02/11 06:00 [entrez]
PHST- 2015/02/11 06:00 [pubmed]
PHST- 2015/10/27 06:00 [medline]
AID - 10.1007/s13277-015-3187-7 [pii]
AID - 10.1007/s13277-015-3187-7 [doi]
PST - ppublish
SO  - Tumour Biol. 2015 Jul;36(7):5273-81. doi: 10.1007/s13277-015-3187-7. Epub 2015 
      Feb 11.