PMID- 36594084
OWN - NLM
STAT- MEDLINE
DCOM- 20230109
LR  - 20230206
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 19
IP  - 1
DP  - 2023
TI  - Inhibition of androgen receptor enhanced the anticancer effects of everolimus 
      through targeting glucose transporter 12.
PG  - 104-119
LID - 10.7150/ijbs.75106 [doi]
AB  - Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It 
      has been proven as a targeted drug for gastric cancer (GC) therapy. However, 
      long-term treatment with everolimus may cause severe side effects for recipients. 
      Decreasing the dosage and attenuating the associated risks are feasible to 
      promote clinical translation of everolimus. This study aimed to identify the 
      underlying mechanisms of responses to everolimus and develop novel regimens for 
      GC treatment. Our findings proved that there was a significant dose-dependent 
      relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. 
      Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was 
      actively upregulated to counteract the anticancer effects of everolimus. GLUT12 
      might be overexpressed in GC. High expression of GLUT12 might be correlated with 
      tumor progression and short survival time of GC patients. Bioinformatic analysis 
      suggested that GLUT12 might be involved in regulating cancer development and 
      metabolism. The experiments proved that GLUT12 significantly promoted GC growth, 
      glycolysis and impaired the anticancer effects of everolimus. Androgen receptor 
      (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated 
      GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated 
      the promotive effects on GLUT12 expression. Both in-vitro and in-vivo experiments 
      demonstrated that GLUT12 knockdown augmented anticancer effects of everolimus. 
      Enzalutamide, an AR inhibitor, or AR knockdown was comparable to GLUT12 
      suppression. This study identified the role of the AR/GLUT12 pathway in the 
      development of poor responses to everolimus. Interference with AR/GLUT12 pathway 
      may serve as a promising approach to promoting the translational application of 
      everolimus in GC therapy.
CI  - (c) The author(s).
FAU - Cao, Bo
AU  - Cao B
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
FAU - Zhao, Ruiyang
AU  - Zhao R
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
FAU - Li, Hanghang
AU  - Li H
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
FAU - Xu, Xingming
AU  - Xu X
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
FAU - Gao, Jingwang
AU  - Gao J
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
FAU - Chen, Lin
AU  - Chen L
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
FAU - Wei, Bo
AU  - Wei B
AD  - Department of General Surgery, First Medical Center, Chinese PLA General 
      Hospital, Beijing 100853, China.
AD  - Medical School of Chinese PLA, Beijing 100853, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230101
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - 9HW64Q8G6G (Everolimus)
RN  - 0 (Glucose Transport Proteins, Facilitative)
RN  - 0 (Receptors, Androgen)
RN  - 0 (SLC2A12 protein, human)
RN  - 0 (AR protein, human)
SB  - IM
MH  - Humans
MH  - Cell Line, Tumor
MH  - *Everolimus/pharmacology
MH  - *Glucose Transport Proteins, Facilitative/metabolism
MH  - *Receptors, Androgen/genetics/metabolism
MH  - Signal Transduction
MH  - *Stomach Neoplasms/drug therapy/genetics
PMC - PMC9760431
OTO - NOTNLM
OT  - Androgen receptor
OT  - Apoptosis
OT  - Everolimus
OT  - Gastric cancer
OT  - Glucose transporter 12
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2023/01/04 06:00
MHDA- 2023/01/05 06:00
PMCR- 2023/01/01
CRDT- 2023/01/03 02:00
PHST- 2022/05/14 00:00 [received]
PHST- 2022/10/08 00:00 [accepted]
PHST- 2023/01/03 02:00 [entrez]
PHST- 2023/01/04 06:00 [pubmed]
PHST- 2023/01/05 06:00 [medline]
PHST- 2023/01/01 00:00 [pmc-release]
AID - ijbsv19p0104 [pii]
AID - 10.7150/ijbs.75106 [doi]
PST - epublish
SO  - Int J Biol Sci. 2023 Jan 1;19(1):104-119. doi: 10.7150/ijbs.75106. eCollection 
      2023.