PMID- 37444561
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231214
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 15
IP  - 13
DP  - 2023 Jun 30
TI  - Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth.
LID - 10.3390/cancers15133451 [doi]
LID - 3451
AB  - Uveal melanoma (UM) displays a high frequency of metastasis; however, effective 
      therapies for metastatic UM are limited. Identifying unique metabolic features of 
      UM may provide a potential targeting strategy. A lipid metabolism protein 
      expression signature was induced in a normal choroidal melanocyte (NCM) line 
      transduced with GNAQ (Q209L), a driver in UM growth and development. 
      Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) 
      compared to NCMs. FASN upregulation was associated with increased mammalian 
      target of rapamycin (mTOR) activation and sterol regulatory element-binding 
      protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced 
      UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell 
      growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA 
      cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that 
      FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling 
      may be considered for treatment of UM.
FAU - Han, Anna
AU  - Han A
AUID- ORCID: 0000-0001-8180-6214
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
AD  - Department of Food Science and Human Nutrition, Jeonbuk National University, 
      Jeonju 54896, Jeollabuk-do, Republic of Korea.
FAU - Mukha, Dzmitry
AU  - Mukha D
AUID- ORCID: 0000-0003-3027-6270
AD  - Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, 
      PA 19104, USA.
FAU - Chua, Vivian
AU  - Chua V
AUID- ORCID: 0000-0002-1873-6820
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Purwin, Timothy J
AU  - Purwin TJ
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Tiago, Manoela
AU  - Tiago M
AUID- ORCID: 0000-0003-0536-2580
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Modasia, Bhavik
AU  - Modasia B
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Baqai, Usman
AU  - Baqai U
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Aumiller, Jenna L
AU  - Aumiller JL
AD  - Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 
      Philadelphia, PA 19107, USA.
FAU - Bechtel, Nelisa
AU  - Bechtel N
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Hunter, Emily
AU  - Hunter E
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
FAU - Danielson, Meggie
AU  - Danielson M
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 
      19107, USA.
FAU - Terai, Mizue
AU  - Terai M
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 
      19107, USA.
FAU - Wedegaertner, Philip B
AU  - Wedegaertner PB
AUID- ORCID: 0000-0001-9264-4759
AD  - Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 
      Philadelphia, PA 19107, USA.
FAU - Sato, Takami
AU  - Sato T
AUID- ORCID: 0000-0003-2221-0415
AD  - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 
      19107, USA.
FAU - Landreville, Solange
AU  - Landreville S
AUID- ORCID: 0000-0002-9164-0657
AD  - Department of Ophthalmology and Otorhinolaryngology-Cervical-Facial Surgery, 
      Faculty of Medicine, Universite Laval, Quebec, QC G1V 0A6, Canada.
FAU - Davies, Michael A
AU  - Davies MA
AUID- ORCID: 0000-0002-0977-0912
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA.
FAU - Kurtenbach, Stefan
AU  - Kurtenbach S
AD  - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33101, USA.
AD  - Sylvester Comprehensive Cancer Center, University of Miami Miller School of 
      Medicine, Miami, FL 33101, USA.
AD  - Interdisciplinary Stem Cell Institute, University of Miami Miller School of 
      Medicine, Miami, FL 33101, USA.
FAU - Harbour, J William
AU  - Harbour JW
AUID- ORCID: 0000-0002-1104-9809
AD  - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33101, USA.
AD  - Sylvester Comprehensive Cancer Center, University of Miami Miller School of 
      Medicine, Miami, FL 33101, USA.
AD  - Interdisciplinary Stem Cell Institute, University of Miami Miller School of 
      Medicine, Miami, FL 33101, USA.
AD  - Department of Ophthalmology, Harold C. Simmons Comprehensive Cancer Center, 
      University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Schug, Zachary T
AU  - Schug ZT
AD  - Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, 
      PA 19104, USA.
FAU - Aplin, Andrew E
AU  - Aplin AE
AD  - Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson 
      University, Philadelphia, PA 19107, USA.
AD  - Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, 
      USA.
LA  - eng
GR  - R01 CA196278/NH/NIH HHS/United States
GR  - R01 CA253977/NH/NIH HHS/United States
GR  - R01 CA196278/CA/NCI NIH HHS/United States
GR  - P30 CA010815/CA/NCI NIH HHS/United States
GR  - P01 CA114046/NH/NIH HHS/United States
GR  - R01 CA253977/CA/NCI NIH HHS/United States
GR  - R01 GM138943/GM/NIGMS NIH HHS/United States
GR  - R01 CA257505/NH/NIH HHS/United States
GR  - DP2 CA249950/CA/NCI NIH HHS/United States
GR  - R50 CA221675/CA/NCI NIH HHS/United States
GR  - P01 CA114046/CA/NCI NIH HHS/United States
GR  - T32 GM144302/GM/NIGMS NIH HHS/United States
GR  - NIH R50CA221675/NH/NIH HHS/United States
GR  - 559058/MRA/Melanoma Research Alliance/United States
GR  - R01 CA257505/CA/NCI NIH HHS/United States
GR  - NCI CA16672/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20230630
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC10341317
OTO - NOTNLM
OT  - GNAQ
OT  - fatty acid synthase
OT  - mTOR pathway
OT  - metabolic inhibition
OT  - uveal melanoma
COIS- A.E. Aplin has ownership interest in patent number 9880150 and has a pending 
      patent, PCT/US22/76492. J.W.H is the inventor of intellectual property related to 
      prognostic testing for uveal melanoma. He is a paid consultant for Castle 
      Biosciences, licensee of this intellectual property, and he receives royalties 
      from its commercialization. M.A.D has been a consultant to Roche/Genentech, 
      Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, 
      Iovance and ABM Therapeutics, and he has been the PI of research grants to MD 
      Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, ABM 
      Therapeutics and LEAD Pharma. The other authors disclose no potential conflict of 
      interest.
EDAT- 2023/07/14 13:06
MHDA- 2023/07/14 13:07
PMCR- 2023/06/30
CRDT- 2023/07/14 01:06
PHST- 2023/06/07 00:00 [received]
PHST- 2023/06/25 00:00 [revised]
PHST- 2023/06/27 00:00 [accepted]
PHST- 2023/07/14 13:07 [medline]
PHST- 2023/07/14 13:06 [pubmed]
PHST- 2023/07/14 01:06 [entrez]
PHST- 2023/06/30 00:00 [pmc-release]
AID - cancers15133451 [pii]
AID - cancers-15-03451 [pii]
AID - 10.3390/cancers15133451 [doi]
PST - epublish
SO  - Cancers (Basel). 2023 Jun 30;15(13):3451. doi: 10.3390/cancers15133451.