PMID- 29719377
OWN - NLM
STAT- MEDLINE
DCOM- 20181011
LR  - 20220317
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 12
DP  - 2018
TI  - Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway 
      involving ERK activation in renal cell carcinoma cells.
PG  - 911-920
LID - 10.2147/DDDT.S160557 [doi]
AB  - AIM: The mammalian target of rapamycin (mTOR) pathway is a critical target for 
      cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for 
      treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 
      has led to the development of drug resistance. Autophagy is closely related to 
      cell survival and death, which may be activated under RAD001 stimulation. The aim 
      of the present study was to identify the underlying mechanisms of RAD001 
      resistance in RCC cells through cytoprotective autophagy involving activation of 
      the extracellular signal-regulated kinase (ERK) pathway. METHODS AND RESULTS: 
      RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent 
      manner, as confirmed by Western blot analysis. Importantly, suppression of 
      autophagy by the pharmacological inhibitor chloroquine effectively enhanced 
      RAD001-induced apoptotic cytotoxicity, as demonstrated by the 
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 
      Western blot analysis, indicating a cytoprotective role for RAD001-induced 
      autophagy. In addition, as was shown by the MTT assay, flow cytometry, and 
      Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal 
      kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor 
      selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. 
      Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and 
      enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced 
      cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated 
      phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot 
      analysis. CONCLUSION: These results suggest that RAD001-induced autophagy 
      involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC 
      cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may 
      be useful to overcome chemoresistance to RAD001.
FAU - Zeng, Yizhou
AU  - Zeng Y
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
FAU - Tian, Xiaofang
AU  - Tian X
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
FAU - Wang, Quan
AU  - Wang Q
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
FAU - He, Weiyang
AU  - He W
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
FAU - Fan, Jing
AU  - Fan J
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
FAU - Gou, Xin
AU  - Gou X
AD  - Department of Urinary Surgery, The First Affiliated Hospital of Chongqing Medical 
      University, Yuzhong District, Chongqing, China.
LA  - eng
PT  - Journal Article
DEP - 20180419
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 0 (AZD 6244)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Autophagy/*drug effects
MH  - Benzimidazoles/pharmacology
MH  - Carcinoma, Renal Cell/*drug therapy/metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Everolimus/chemistry/*pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/*metabolism
MH  - Flow Cytometry
MH  - Humans
MH  - Kidney Neoplasms/*drug therapy/metabolism/pathology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
PMC - PMC5914548
OTO - NOTNLM
OT  - ERK
OT  - apoptosis
OT  - autophagy
OT  - everolimus
OT  - renal cancer
OT  - selumetinib
COIS- Disclosure The authors report no conflicts of interest in this work.
EDAT- 2018/05/03 06:00
MHDA- 2018/10/12 06:00
PMCR- 2018/04/19
CRDT- 2018/05/03 06:00
PHST- 2018/05/03 06:00 [entrez]
PHST- 2018/05/03 06:00 [pubmed]
PHST- 2018/10/12 06:00 [medline]
PHST- 2018/04/19 00:00 [pmc-release]
AID - dddt-12-911 [pii]
AID - 10.2147/DDDT.S160557 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2018 Apr 19;12:911-920. doi: 10.2147/DDDT.S160557. 
      eCollection 2018.