PMID- 30848009
OWN - NLM
STAT- MEDLINE
DCOM- 20190617
LR  - 20210109
IS  - 1365-2184 (Electronic)
IS  - 0960-7722 (Print)
IS  - 0960-7722 (Linking)
VI  - 52
IP  - 3
DP  - 2019 May
TI  - Rab25 promotes erlotinib resistance by activating the beta1 integrin/AKT/beta-catenin 
      pathway in NSCLC.
PG  - e12592
LID - 10.1111/cpr.12592 [doi]
LID - e12592
AB  - OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) 
      has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) 
      patients. However, acquired resistance is inevitable and limits the long-term 
      efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated 
      binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC. MATERIALS 
      AND METHODS: Rab25 expression in NSCLC patients was measured by 
      immunohistochemical staining. Western blotting was used to analyse the expression 
      of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors 
      were constructed to knock in and knock out Rab25. The biological function of 
      Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction 
      between Rab25 and beta1 integrin was confirmed by co-immunoprecipitation. RESULTS: 
      Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown 
      reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with 
      beta1 integrin and promotes its trafficking to the cytoplasmic membrane. The 
      membrane-beta1 integrin induced protein kinase B (AKT) phosphorylation and 
      subsequently activated the Wnt/beta-catenin signalling pathway, promoting cell 
      proliferation. Furthermore, high Rab25 expression was associated with poor 
      response to EGFR-TKI treatment in NSCLC patients. CONCLUSIONS: Rab25 mediates 
      erlotinib resistance by activating the beta1 integrin/AKT/beta-catenin signalling 
      pathway. Rab25 may be a predictive biomarker and has potential therapeutic value 
      in NSCLC patients with acquired resistance to EGFR-TKI.
CI  - (c) 2019 The Authors Cell Proliferation Published by John Wiley & Sons Ltd.
FAU - Wang, Jianmin
AU  - Wang J
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Zhou, Pu
AU  - Zhou P
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Wang, Xudong
AU  - Wang X
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Yu, Yongxin
AU  - Yu Y
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Zhu, Guangkuo
AU  - Zhu G
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Zheng, Linpeng
AU  - Zheng L
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Xu, Zihan
AU  - Xu Z
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Li, Feng
AU  - Li F
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - You, Qiai
AU  - You Q
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Yang, Qiao
AU  - Yang Q
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Zhuo, Wenlei
AU  - Zhuo W
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Sun, Jianguo
AU  - Sun J
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
FAU - Chen, Zhengtang
AU  - Chen Z
AUID- ORCID: 0000-0001-6862-9380
AD  - Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
LA  - eng
GR  - 81672841/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20190307
PL  - England
TA  - Cell Prolif
JT  - Cell proliferation
JID - 9105195
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (Integrin beta1)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Rab25 protein, human)
RN  - 0 (beta Catenin)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.5.2 (rab GTP-Binding Proteins)
SB  - IM
MH  - Adenocarcinoma of Lung/drug therapy/metabolism
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/*metabolism
MH  - Drug Resistance, Neoplasm
MH  - Erlotinib Hydrochloride/*pharmacology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Integrin beta1/metabolism
MH  - Lung Neoplasms/*drug therapy/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/drug effects
MH  - Xenograft Model Antitumor Assays
MH  - beta Catenin/metabolism
MH  - rab GTP-Binding Proteins/antagonists & inhibitors/genetics/*metabolism
PMC - PMC6536583
OTO - NOTNLM
OT  - EGFR-TKI resistance
OT  - NSCLC
OT  - Rab25
OT  - beta-catenin
OT  - beta1 integrin
COIS- All authors declared no conflicts of interest.
EDAT- 2019/03/09 06:00
MHDA- 2019/06/18 06:00
PMCR- 2019/03/07
CRDT- 2019/03/09 06:00
PHST- 2019/01/02 00:00 [received]
PHST- 2019/01/23 00:00 [revised]
PHST- 2019/01/30 00:00 [accepted]
PHST- 2019/03/09 06:00 [pubmed]
PHST- 2019/06/18 06:00 [medline]
PHST- 2019/03/09 06:00 [entrez]
PHST- 2019/03/07 00:00 [pmc-release]
AID - CPR12592 [pii]
AID - 10.1111/cpr.12592 [doi]
PST - ppublish
SO  - Cell Prolif. 2019 May;52(3):e12592. doi: 10.1111/cpr.12592. Epub 2019 Mar 7.