PMID- 34540820
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210921
IS  - 2296-634X (Print)
IS  - 2296-634X (Electronic)
IS  - 2296-634X (Linking)
VI  - 9
DP  - 2021
TI  - Co-treatment With Everolimus, an mTOR-Specific Antagonist, or Downregulation of 
      ELK1 Enhances the Sensitivity of Pancreatic Cancer Cells to Genistein.
PG  - 633035
LID - 10.3389/fcell.2021.633035 [doi]
LID - 633035
AB  - Genistein is a natural isoflavone with pharmacological or potentially anti-tumor 
      properties. However, the resistance of cancer cells to genistein remains a major 
      obstacle. This study focused on the mechanism implicated in the resistance of 
      pancreatic cancer (PC) cells to genistein and the mechanism of action. First, key 
      molecules and signaling pathways related to genistein resistance in PC cells were 
      explored using bioinformatics tools. DEP domain containing MTOR interacting 
      protein (DEPTOR), a typical inhibitor of the mammalian target of rapamycin (mTOR) 
      signaling, was predicted to be poorly expressed in the genistein-resistant PC 
      cells. Thereafter, genistein-resistant PC cells (Panc-1 and PaCa) were 
      constructed. Altered expression of DEPTOR was introduced in cells, and everolimus 
      (ELM), an mTOR-specific antagonist, was administrated in cells as well to examine 
      their roles in genistein resistance. The cell apoptosis was examined in vitro and 
      in vivo in mouse xenograft tumors. The upstream regulator of DEPTOR was predicted 
      via bioinformatic tools. The bioinformatic analyses showed that the PI3K/AKT/mTOR 
      signaling pathway was activated in the setting of DEPTOR downregulation in 
      genistein-resistant PC cells. DEPTOR overexpression reduced the 50% inhibiting 
      concentration (IC50) of genistein in PC cells and suppressed mTOR 
      phosphorylation, and it increased caspase-3 activity, LDH release and apoptosis 
      in PC cells. ELM treatment enhanced the sensitivity of PC cells to genistein in 
      vitro and it strengthened the tumor-eliminating role of genistein in mice. ETS 
      transcription factor ELK1 (ELK1), a transcription factor that negatively 
      regulated DEPTOR transcription, was suppressed by genistein. Upregulation of ELK1 
      suppressed DEPTOR transcription and reduced the genistein sensitivity of cells, 
      and it also blocked the genistein-sensitizing roles of ELM in PC cells. In 
      conclusion, this study demonstrated that ELK1 reduces DEPTOR transcription, 
      leading to mTOR phosphorylation and the drug resistance of PC cells.
CI  - Copyright (c) 2021 Li, Kuang, Yang, Zhang, Zhang and Fan.
FAU - Li, Tianyu
AU  - Li T
AD  - Department of Integrated Traditional Chinese Medicine and Western Medicine, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Kuang, Tiantao
AU  - Kuang T
AD  - Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Yang, Zhaoshuo
AU  - Yang Z
AD  - Department of Integrated Traditional Chinese Medicine and Western Medicine, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Zhang, Qiqi
AU  - Zhang Q
AD  - Department of Integrated Traditional Chinese Medicine and Western Medicine, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Zhang, Wen
AU  - Zhang W
AD  - Department of Integrated Traditional Chinese Medicine and Western Medicine, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Fan, Yue
AU  - Fan Y
AD  - Department of Integrated Traditional Chinese Medicine and Western Medicine, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
AD  - Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20210903
PL  - Switzerland
TA  - Front Cell Dev Biol
JT  - Frontiers in cell and developmental biology
JID - 101630250
PMC - PMC8448347
OTO - NOTNLM
OT  - DEPTOR
OT  - Elk1
OT  - everolimus
OT  - genistein
OT  - mTOR
OT  - pancreatic cancer
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/09/21 06:00
MHDA- 2021/09/21 06:01
PMCR- 2021/01/01
CRDT- 2021/09/20 06:14
PHST- 2020/11/24 00:00 [received]
PHST- 2021/08/06 00:00 [accepted]
PHST- 2021/09/20 06:14 [entrez]
PHST- 2021/09/21 06:00 [pubmed]
PHST- 2021/09/21 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcell.2021.633035 [doi]
PST - epublish
SO  - Front Cell Dev Biol. 2021 Sep 3;9:633035. doi: 10.3389/fcell.2021.633035. 
      eCollection 2021.