PMID- 31586300
OWN - NLM
STAT- MEDLINE
DCOM- 20200804
LR  - 20211204
IS  - 1749-0774 (Electronic)
IS  - 0914-7470 (Print)
IS  - 0914-7470 (Linking)
VI  - 33
IP  - 1
DP  - 2020 Jan
TI  - mTOR inhibitor everolimus reduces invasiveness of melanoma cells.
PG  - 88-97
LID - 10.1007/s13577-019-00270-4 [doi]
AB  - The mammalian target of rapamycin (mTOR) plays a key role in several cellular 
      processes: proliferation, survival, invasion, and angiogenesis, and therefore, 
      controls cell behavior both in health and in disease. Dysregulation of the mTOR 
      signaling is involved in some of the cancer hallmarks, and thus the mTOR pathway 
      is an important target for the development of a new anticancer therapy. The 
      object of this study is recognition of the possible role of mTOR kinase 
      inhibitors-everolimus single and in combination with selected downstream protein 
      kinases inhibitors: LY294002 (PI3 K), U0126 (ERK1/2), GDC-0879 (B-RAF), AS-703026 
      (MEK), MK-2206 (AKT), PLX-4032 (B-RRAF) in cell invasion in malignant melanoma. 
      Treatment of melanoma cells with everolimus led to a significant decrease in the 
      level of both phosphorylated: mTOR (Ser2448) and mTOR (Ser2481) as well as their 
      downstream effectors. The use of protein kinase inhibitors produced a significant 
      decrease in metalloproteinases (MMPs) activity, as well as diminished invasion, 
      especially when used in combination. The best results in the inhibition of both 
      MMPs and cell invasiveness were obtained for the combination of an mTOR 
      inhibitor- everolimus with a B-RAF inhibitor-PLX-4032. Slightly less profound 
      reduction of invasiveness was obtained for the combinations of an mTOR 
      inhibitor-everolimus with ERK1/2 inhibitor-U126 or MEK inhibitor-AS-703026 and in 
      the case of MMPs activity decrease for PI3 K inhibitor-LY294002 and AKT 
      inhibitor-MK-2206. The simultaneous use of everolimus or another new generation 
      rapalog with selected inhibitors of crucial signaling kinases seems to be a 
      promising concept in cancer treatment.
FAU - Ciolczyk-Wierzbicka, Dorota
AU  - Ciolczyk-Wierzbicka D
AUID- ORCID: 0000-0003-2631-7308
AD  - Chair of Medical Biochemistry, Jagiellonian University Medical College, ul. 
      Kopernika 7, 31-034, Krakow, Poland. mbciolcz@cyf-kr.edu.pl.
FAU - Gil, Dorota
AU  - Gil D
AD  - Chair of Medical Biochemistry, Jagiellonian University Medical College, ul. 
      Kopernika 7, 31-034, Krakow, Poland.
FAU - Zarzycka, Marta
AU  - Zarzycka M
AD  - Chair of Medical Biochemistry, Jagiellonian University Medical College, ul. 
      Kopernika 7, 31-034, Krakow, Poland.
FAU - Laidler, Piotr
AU  - Laidler P
AD  - Chair of Medical Biochemistry, Jagiellonian University Medical College, ul. 
      Kopernika 7, 31-034, Krakow, Poland.
LA  - eng
GR  - CCBY/Uniwersytet Jagiellonski Collegium Medicum/
PT  - Journal Article
DEP - 20191004
PL  - Japan
TA  - Hum Cell
JT  - Human cell
JID - 8912329
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Everolimus/*pharmacology
MH  - Humans
MH  - Melanoma/*pathology
MH  - Neoplasm Invasiveness
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC6965047
OTO - NOTNLM
OT  - Cell invasion
OT  - Melanoma
OT  - Protein kinase inhibitors
OT  - mTOR
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/10/06 06:00
MHDA- 2020/08/05 06:00
PMCR- 2019/10/04
CRDT- 2019/10/06 06:00
PHST- 2019/02/04 00:00 [received]
PHST- 2019/07/17 00:00 [accepted]
PHST- 2019/10/06 06:00 [pubmed]
PHST- 2020/08/05 06:00 [medline]
PHST- 2019/10/06 06:00 [entrez]
PHST- 2019/10/04 00:00 [pmc-release]
AID - 10.1007/s13577-019-00270-4 [pii]
AID - 270 [pii]
AID - 10.1007/s13577-019-00270-4 [doi]
PST - ppublish
SO  - Hum Cell. 2020 Jan;33(1):88-97. doi: 10.1007/s13577-019-00270-4. Epub 2019 Oct 4.