PMID- 36388085
OWN - NLM
STAT- MEDLINE
DCOM- 20221121
LR  - 20221121
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 16
DP  - 2022
TI  - Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired 
      Docetaxel Resistance.
PG  - 3817-3828
LID - 10.2147/DDDT.S376474 [doi]
AB  - PURPOSE: Mammalian Target of rapamycin (mTOR) plays a central role in regulating 
      cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly 
      expressed in docetaxel-resistant prostate cells. However, the underlying 
      molecular effects on prostate cells remain unclear. METHODS: A 
      docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to 
      investigate the role of mTORC2 in docetaxel resistance. The lentivirus was 
      transfected into cells to knock down the expression of Rictor, and cell viability 
      was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze 
      the cell cycle, and the changes in related signal cascades were assessed by 
      immunohistochemistry (IHC) staining and Western blot. RESULTS: Docetaxel showed 
      the lowest IC(50) (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. 
      Decreased Rictor expression resulted in a larger proportion of arrested cells in 
      the G0/G1 phase in PC-3/DTX cells. The IC(50) values of the AZD8055 group were 
      lower than in the Rapamycin group when treated with docetaxel again. Furthermore, 
      a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the 
      AZD8055 group compared to the Rapamycin group. The IHC results of the prostate 
      cancer tissues from a CRPC patient revealed the over expression of Rictor only, 
      while Raptor expression was unaffected. CONCLUSION: We investigated the role of 
      mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify 
      potential methods for clinical treatment. MTORC2 expression is essential for 
      docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused 
      more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor 
      Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, 
      reversing docetaxel resistance, may become a therapeutic option in the treatment 
      of mCRPC patients.
CI  - (c) 2022 Huang et al.
FAU - Huang, Yujie
AU  - Huang Y
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
FAU - Zhai, You
AU  - Zhai Y
AUID- ORCID: 0000-0002-7972-1462
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
FAU - Wu, Meijia
AU  - Wu M
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
FAU - Chang, Chengdong
AU  - Chang C
AD  - Department of Pathology, The First Affiliated Hospital, Zhejiang University 
      School of Medicine, Hangzhou, People's Republic of China.
FAU - Luo, Jindan
AU  - Luo J
AD  - Department of Urology, The First Affiliated Hospital, Zhejiang University School 
      of Medicine, Hangzhou, People's Republic of China.
FAU - Hong, Dongsheng
AU  - Hong D
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
FAU - Zhao, Qingwei
AU  - Zhao Q
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
FAU - Dai, Yao
AU  - Dai Y
AD  - Department of Radiation Oncology, College of Medicine, University of Florida, 
      Gainesville, FL, USA.
FAU - Liu, Jian
AU  - Liu J
AUID- ORCID: 0000-0001-6882-0468
AD  - Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for 
      Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20221104
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 15H5577CQD (Docetaxel)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Male
MH  - Humans
MH  - Docetaxel/pharmacology
MH  - *Prostatic Neoplasms, Castration-Resistant/drug therapy
MH  - Cell Line, Tumor
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Sirolimus/pharmacology
PMC - PMC9642805
OTO - NOTNLM
OT  - docetaxel
OT  - drug resistance
OT  - mTORC2
OT  - prostate cancer cell
OT  - reverse
COIS- The authors declared that no conflicts of interest exist for this article.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/22 06:00
PMCR- 2022/11/04
CRDT- 2022/11/17 12:06
PHST- 2022/06/10 00:00 [received]
PHST- 2022/10/24 00:00 [accepted]
PHST- 2022/11/17 12:06 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/22 06:00 [medline]
PHST- 2022/11/04 00:00 [pmc-release]
AID - 376474 [pii]
AID - 10.2147/DDDT.S376474 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2022 Nov 4;16:3817-3828. doi: 10.2147/DDDT.S376474. 
      eCollection 2022.