PMID- 25153728
OWN - NLM
STAT- MEDLINE
DCOM- 20151221
LR  - 20211203
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 5
IP  - 15
DP  - 2014 Aug 15
TI  - The anti-tumor activator sMEK1 and paclitaxel additively decrease expression of 
      HIF-1alpha and VEGF via mTORC1-S6K/4E-BP-dependent signaling pathways.
PG  - 6540-51
AB  - Recently, we found that sMEK1 effectively regulates pro-apoptotic activity when 
      combined with a traditional chemotherapeutic drug. Therefore, combinational 
      therapeutic strategies targeting critical molecular and cellular mechanisms are 
      urgently required. In this present work, we evaluated whether sMEK1 enhanced the 
      pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. 
      Combined with a chemotherapeutic drug, sMEK1 showed an additive effect on the 
      suppression of ovarian cancer cell growth by inducing cell cycle arrest and 
      apoptosis and regulating related gene expression levels or protein activities. In 
      addition, the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin 
      (mTOR) pathway was strongly inhibited by the combined treatment, showing 
      de-repression of the tuberous sclerosis complex (TSC) and suppression of ras 
      homolog enriched in the brain (Rheb) and mTOR and raptor in aggressive ovarian 
      carcinoma cells and mouse xenograft models. Treatment with sMEK1 and paclitaxel 
      reduced phosphorylation of ribosomal S6 kinase (S6K) and 4E-binding protein 
      (4E-BP), two critical downstream targets of the mTOR-signaling pathway. 
      Furthermore, both sMEK1 and paclitaxel significantly inhibited the expression of 
      signaling components downstream of S6K/4E-BP, such as hypoxia-inducible factor-1alpha 
      (HIF-1alpha) and vascular endothelial growth factor (VEGF), both in vitro and in 
      vivo. Therefore, our data suggest that the combination of sMEK1 and paclitaxel is 
      a promising and effective targeted therapy for chemotherapy-resistant or 
      recurrent ovarian cancers.
FAU - Kim, Boh-Ram
AU  - Kim BR
AD  - Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, 
      Goyang-si Gyeonggi-do, Republic of Korea; These Authors contributed equally to 
      this work.
FAU - Yoon, Kyungsil
AU  - Yoon K
AD  - Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, 
      Goyang-si Gyeonggi-do, Republic of Korea; These Authors contributed equally to 
      this work.
FAU - Byun, Hyun-Jung
AU  - Byun HJ
AD  - Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, 
      Goyang-si Gyeonggi-do, Republic of Korea.
FAU - Seo, Seung Hee
AU  - Seo SH
AD  - Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, 
      Goyang-si Gyeonggi-do, Republic of Korea.
FAU - Lee, Seung-Hoon
AU  - Lee SH
AD  - Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, 
      Yongin-si Gyeonggi-do, Republic of Korea.
FAU - Rho, Seung Bae
AU  - Rho SB
AD  - Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, 
      Goyang-si Gyeonggi-do, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (PPP4R3A protein, human)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Ovarian Epithelial
MH  - Cell Cycle Checkpoints/drug effects
MH  - Cell Cycle Proteins
MH  - Cell Movement/drug effects
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Multiprotein Complexes/metabolism
MH  - Neoplasms, Glandular and Epithelial/*drug therapy/genetics/*metabolism/pathology
MH  - Ovarian Neoplasms/*drug therapy/genetics/*metabolism/pathology
MH  - Paclitaxel/administration & dosage
MH  - Phosphoprotein Phosphatases/administration & dosage
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Vascular Endothelial Growth Factor A/*biosynthesis
PMC - PMC4171649
COIS- The authors declare no conflict of interest.
EDAT- 2014/08/26 06:00
MHDA- 2015/12/22 06:00
PMCR- 2014/08/01
CRDT- 2014/08/26 06:00
PHST- 2014/08/26 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2015/12/22 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 2119 [pii]
AID - 10.18632/oncotarget.2119 [doi]
PST - ppublish
SO  - Oncotarget. 2014 Aug 15;5(15):6540-51. doi: 10.18632/oncotarget.2119.