PMID- 29755672
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 29
DP  - 2018 Apr 17
TI  - Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma.
PG  - 20563-20577
LID - 10.18632/oncotarget.25003 [doi]
AB  - The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine 
      kinase that mediates intracellular metabolism, cell survival and actin 
      rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, 
      activated by the scaffold proteins RAPTOR and RICTOR, respectively. The 
      activation of mTORC1 triggers protein synthesis and autophagy inhibition, while 
      mTORC2 activation promotes progression, survival, actin reorganization, and drug 
      resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal 
      role in the survival of tumor cells, we evaluated its activation in endothelial 
      cells (ECs) from 20 patients with monoclonal gammopathy of undetermined 
      significance (MGUS) and 47 patients with multiple myeloma (MM), and its 
      involvement in angiogenesis. MM-ECs showed a significantly higher expression of 
      mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation 
      of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the 
      angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA 
      targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic 
      functions, including cell migration, chemotaxis, adhesion, invasion, in vitro 
      angiogenesis on Matrigel((R)), and cytoskeleton reorganization. In addition, PP242 
      treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic 
      Membrane (CAM) and Matrigel((R)) plug assays. PP242 exhibited a synergistic effect 
      with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the 
      anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is 
      involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may 
      be useful for the anti-angiogenic management of MM patients.
FAU - Lamanuzzi, Aurelia
AU  - Lamanuzzi A
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Saltarella, Ilaria
AU  - Saltarella I
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Desantis, Vanessa
AU  - Desantis V
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Frassanito, Maria Antonia
AU  - Frassanito MA
AD  - Department of Biomedical Sciences and Human Oncology, General Pathology Unit, 
      University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Leone, Patrizia
AU  - Leone P
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Racanelli, Vito
AU  - Racanelli V
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Nico, Beatrice
AU  - Nico B
AD  - Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section 
      of Human Anatomy and Histology, University of Bari Aldo Moro Medical School, 
      Bari, Italy.
FAU - Ribatti, Domenico
AU  - Ribatti D
AD  - Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section 
      of Human Anatomy and Histology, University of Bari Aldo Moro Medical School, 
      Bari, Italy.
AD  - National Cancer Institute Giovanni Paolo II, Bari, Italy.
FAU - Ditonno, Paolo
AU  - Ditonno P
AD  - Hematology Unit, Di Venere Hospital, Bari, Italy.
FAU - Prete, Marcella
AU  - Prete M
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Solimando, Antonio Giovanni
AU  - Solimando AG
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Dammacco, Francesco
AU  - Dammacco F
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Vacca, Angelo
AU  - Vacca A
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
FAU - Ria, Roberto
AU  - Ria R
AD  - Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. 
      Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
LA  - eng
PT  - Journal Article
DEP - 20180417
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5945497
OTO - NOTNLM
OT  - PP242
OT  - angiogenesis
OT  - endothelial cells
OT  - mTOR
OT  - multiple myeloma
COIS- CONFLICTS OF INTEREST The authors declare that there are no competing financial 
      interests in relation to this work.
EDAT- 2018/05/15 06:00
MHDA- 2018/05/15 06:01
PMCR- 2018/04/17
CRDT- 2018/05/15 06:00
PHST- 2017/06/08 00:00 [received]
PHST- 2018/03/13 00:00 [accepted]
PHST- 2018/05/15 06:00 [entrez]
PHST- 2018/05/15 06:00 [pubmed]
PHST- 2018/05/15 06:01 [medline]
PHST- 2018/04/17 00:00 [pmc-release]
AID - 25003 [pii]
AID - 10.18632/oncotarget.25003 [doi]
PST - epublish
SO  - Oncotarget. 2018 Apr 17;9(29):20563-20577. doi: 10.18632/oncotarget.25003. 
      eCollection 2018 Apr 17.