PMID- 37772579
OWN - NLM
STAT- MEDLINE
DCOM- 20231002
LR  - 20231002
IS  - 1791-7530 (Electronic)
IS  - 0250-7005 (Linking)
VI  - 43
IP  - 10
DP  - 2023 Oct
TI  - Molecular Characteristics of Everolimus-resistant Renal Cell Carcinoma Cells 
      Generated by Continuous Exposure to Everolimus.
PG  - 4349-4357
LID - 10.21873/anticanres.16630 [doi]
AB  - BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) inhibitors represent the 
      standard of care for metastatic renal cell carcinoma (RCC). However, treatment 
      outcomes are relatively poor, suggesting a potential problem with tolerating mTOR 
      inhibitors. The aim of this study was to establish everolimus-resistant sublines 
      and to compare their molecular characteristics with those of their counterparts. 
      MATERIALS AND METHODS: Human-derived RCC, Caki-2, and 786-O cells were 
      continuously exposed to everolimus at 1 muM, and the established resistant 
      sublines were designated as Caki/EV and 786/EV, respectively. Cellular 
      characteristics were compared between both cells. RESULTS: Caki/EV and 786/EV 
      cells showed a decrease in sensitivity to everolimus as well as other mTOR 
      inhibitors. Expression of mTOR and its effectors exhibited no alteration in 
      resistant sublines and their counterparts. However, phosphorylation of S6K, an 
      index of mTOR activity, decreased in resistant sublines. PCR array analysis of 
      mTOR signaling pathway-related factors indicated that the expression of INSR, 
      TP53, and IGFBP3 increased in Caki/EV cells, whereas that of TELO2, HRAS, and 
      SGK1 was up-regulated in 786/EV cells. The levels of DDIT4, DEPTOR, HIF1A, and 
      PLD1 mRNAs decreased in both cell lines. CONCLUSION: The novel 
      everolimus-resistant Caki/EV and 786/EV cells exhibited cross-resistance to other 
      mTOR inhibitors and decreased mTOR activity. Furthermore, down-regulation of 
      DDIT4, DEPTOR, HIF1A, and PLD1 may contribute to everolimus resistance.
CI  - Copyright (c) 2023 International Institute of Anticancer Research (Dr. George J. 
      Delinasios), All rights reserved.
FAU - Nakayama, Yuko
AU  - Nakayama Y
AD  - Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji 
      Dokkyo University, Himeji, Japan.
FAU - Enomoto, Daichi
AU  - Enomoto D
AD  - Department of Pharmaceutics and Pharmaceutical Technology, Faculty of 
      Pharmaceutical Sciences, Hyogo Medical University, Kobe, Japan.
FAU - Yamamoto, Kazuhiro
AU  - Yamamoto K
AD  - Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
FAU - Takara, Kohji
AU  - Takara K
AD  - Department of Pharmaceutics and Pharmaceutical Technology, Faculty of 
      Pharmaceutical Sciences, Hyogo Medical University, Kobe, Japan; 
      ko-takara@hyo-med.ac.jp.
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
RN  - 9HW64Q8G6G (Everolimus)
RN  - 0 (MTOR Inhibitors)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (DEPTOR protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
SB  - IM
MH  - Humans
MH  - Everolimus/pharmacology/therapeutic use
MH  - *Carcinoma, Renal Cell/drug therapy/genetics/metabolism
MH  - *Kidney Neoplasms/drug therapy/genetics/metabolism
MH  - MTOR Inhibitors
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Cell Line, Tumor
MH  - Intracellular Signaling Peptides and Proteins
OTO - NOTNLM
OT  - Everolimus
OT  - mTOR
OT  - multidrug resistance
OT  - renal cell carcinoma
EDAT- 2023/09/29 12:44
MHDA- 2023/10/02 06:42
CRDT- 2023/09/29 07:31
PHST- 2023/07/11 00:00 [received]
PHST- 2023/08/03 00:00 [revised]
PHST- 2023/08/04 00:00 [accepted]
PHST- 2023/10/02 06:42 [medline]
PHST- 2023/09/29 12:44 [pubmed]
PHST- 2023/09/29 07:31 [entrez]
AID - 43/10/4349 [pii]
AID - 10.21873/anticanres.16630 [doi]
PST - ppublish
SO  - Anticancer Res. 2023 Oct;43(10):4349-4357. doi: 10.21873/anticanres.16630.