PMID- 29077243
OWN - NLM
STAT- MEDLINE
DCOM- 20180123
LR  - 20210109
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 109
IP  - 1
DP  - 2018 Jan
TI  - Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising 
      therapeutic target for adult T-cell leukemia.
PG  - 103-111
LID - 10.1111/cas.13431 [doi]
AB  - Adult T-cell leukemia (ATL) has a poor prognosis as a result of severe 
      immunosuppression and rapid tumor progression with resistance to conventional 
      chemotherapy. Recent integrated-genome analysis has revealed mutations in many 
      genes involved in the T-cell signaling pathway, suggesting that the aberration of 
      this pathway is an important factor in ATL pathogenesis and ATL-cell 
      proliferation. We screened a siRNA library to examine signaling-pathway 
      functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell 
      proliferation. We therefore investigated the effect of mammalian target of 
      rapamycin (mTOR) inhibitors, including the dual inhibitors PP242 and AZD8055 and 
      the mTORC1 inhibitors rapamycin and everolimus, on human T-cell leukemia virus 
      type 1 (HTLV-1)-infected-cell and ATL-cell lines. Both dual inhibitors inhibited 
      the proliferation of all tested cell lines by inducing G1-phase cell-cycle arrest 
      and subsequent cell apoptosis, whereas the effects of the 2 mTORC1 inhibitors 
      were limited, as they did not induce cell apoptosis. In the ATL-cell lines and in 
      the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at 
      serine-473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 
      inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly 
      inhibited the in vivo growth of the ATL-cell xenografts than did everolimus. 
      These results indicate that the PI3K/mTOR pathway is critical to ATL-cell 
      proliferation and might thus be a new therapeutic target in ATL.
CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Kawata, Takahito
AU  - Kawata T
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Tada, Kohei
AU  - Tada K
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Kobayashi, Masayuki
AU  - Kobayashi M
AUID- ORCID: 0000-0001-8733-8458
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Sakamoto, Takashi
AU  - Sakamoto T
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Takiuchi, Yoko
AU  - Takiuchi Y
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Iwai, Fumie
AU  - Iwai F
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Sakurada, Maki
AU  - Sakurada M
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Hishizawa, Masakatsu
AU  - Hishizawa M
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Shirakawa, Kotaro
AU  - Shirakawa K
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Shindo, Keisuke
AU  - Shindo K
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
FAU - Sato, Hironori
AU  - Sato H
AD  - Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, 
      Japan.
FAU - Takaori-Kondo, Akifumi
AU  - Takaori-Kondo A
AD  - Department of Hematology and Oncology, Graduate School of Medicine, Kyoto 
      University, Kyoto, Japan.
LA  - eng
PT  - Journal Article
DEP - 20171122
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Indoles)
RN  - 0 (Morpholines)
RN  - 0 (Purines)
RN  - 0 (RNA, Small Interfering)
RN  - 970JJ37FPW 
      ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol)
RN  - 9HW64Q8G6G (Everolimus)
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  - H5669VNZ7V (PP242)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & 
      dosage/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Everolimus/administration & dosage/pharmacology
MH  - Humans
MH  - Indoles/administration & dosage/pharmacology
MH  - Leukemia-Lymphoma, Adult T-Cell/*drug therapy/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors
MH  - Mechanistic Target of Rapamycin Complex 2/*antagonists & inhibitors
MH  - Mice
MH  - Morpholines/administration & dosage/pharmacology
MH  - Phosphorylation/drug effects
MH  - Purines/administration & dosage/pharmacology
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC5765289
OTO - NOTNLM
OT  - Akt
OT  - HTLV-1
OT  - adult T-cell leukemia
OT  - mTOR
OT  - mTORC
EDAT- 2017/10/28 06:00
MHDA- 2018/01/24 06:00
PMCR- 2018/01/01
CRDT- 2017/10/28 06:00
PHST- 2017/07/24 00:00 [received]
PHST- 2017/10/17 00:00 [revised]
PHST- 2017/10/21 00:00 [accepted]
PHST- 2017/10/28 06:00 [pubmed]
PHST- 2018/01/24 06:00 [medline]
PHST- 2017/10/28 06:00 [entrez]
PHST- 2018/01/01 00:00 [pmc-release]
AID - CAS13431 [pii]
AID - 10.1111/cas.13431 [doi]
PST - ppublish
SO  - Cancer Sci. 2018 Jan;109(1):103-111. doi: 10.1111/cas.13431. Epub 2017 Nov 22.