PMID- 26041383
OWN - NLM
STAT- MEDLINE
DCOM- 20160826
LR  - 20220409
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 93
IP  - 11
DP  - 2015 Nov
TI  - Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis 
      via cytochrome P450 1B1.
PG  - 1221-33
LID - 10.1007/s00109-015-1300-4 [doi]
AB  - Smoking carcinogen N-nitrosamines such as 
      4-methylnitrosamino-l-3-pyridyl-butanone (NNK) require metabolic activation to 
      exert their genotoxicity. The first activation step is mainly catalyzed by 
      cytochrome P450 (CYP) family. Estrogen receptor alpha (ERalpha) plays a role in lung 
      pathology. The association between them is unknown. In this study, we explored 
      the relationship and function of CYP1B1 and ERalpha in NNK-induced lung 
      tumorigenesis. CYP1B1 and ERalpha expression was analyzed in human lung cancer 
      tissues and NNK-induced lung tumor of A/J mice. Cell lines NCI-H23 and NCI-H460 
      were employed to further study the responsible mechanisms using various cellular 
      and molecular approaches. Our in vivo experiments demonstrated that CYP1B1 and 
      ERalpha were over-expressed at the early stage of NNK-induced lung tumorigenesis. 
      Microarray analysis found that ERalpha was involved in the 
      extracellular-signal-regulated kinase (ERK)/MAPK pathway. NNK activated 
      RAS/ERK/AP1 as it remarkably increased the levels of p-ERK, c-Fos, and c-Jun but 
      inhibited multiple negative regulators of Ras/ERK/AP1, Pdcd4, Spry1, Spry2, and 
      Btg2 through up-regulating miR-21. Both CYP1B1 siRNA and ERK-specific inhibitor 
      U0126 suppressed NNK-mediated ERalpha up-regulation, suggesting that ERalpha was 
      downstream of CYP1B1 and ERK. ERK inactivation led to the accumulation of CYP1B1, 
      indicating that CYP1B1 was upstream of ERK activation. Inhibition of ERK or ERalpha 
      decreased NNK-induced cell proliferation. Blockage of CYP1B1 or ERalpha induced 
      apoptosis of lung cancer cells. Collectively, NNK-mediated ERalpha induction is via 
      CYP1B1 and ERK and contributes to the lung carcinogenesis. The inhibition of 
      CYP1B1, ERK, or ERalpha may arrest the lung cancer cell growth, implicating a pivotal 
      strategy for the treatment of lung cancer. KEY MESSAGES: Smoking carcinogen NNK 
      requires metabolic activation to exert their genotoxicity. CYP1B1 is the enzyme 
      to catalyze NNK. NNK activates CYP1B1 and ERK to induce ERalpha. Inhibition of 
      CYP1B1, ERK, or ERalpha arrests the lung cancer cell growth.
FAU - Li, Ming-Yue
AU  - Li MY
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Liu, Yi
AU  - Liu Y
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
AD  - Guangdong Medical College, Zhangjiang, Guangdong, China.
FAU - Liu, Li-Zhong
AU  - Liu LZ
AD  - Department of Pathophysiology, Faculty of Medicine, Shenzhen University Health 
      Science Center, Shenzhen University, Shenzhen, China.
FAU - Kong, Angel W Y
AU  - Kong AW
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Zhao, Zhili
AU  - Zhao Z
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Wu, Bin
AU  - Wu B
AD  - Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical 
      College, Zhanjiang, Guangdong, China.
FAU - Long, Xiang
AU  - Long X
AD  - Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
FAU - Wu, Jun
AU  - Wu J
AD  - Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical 
      College, Zhanjiang, Guangdong, China.
FAU - Ng, Calvin S H
AU  - Ng CS
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Wan, Innes Y P
AU  - Wan IY
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Du, Jing
AU  - Du J
AD  - Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
FAU - Mok, Tony S K
AU  - Mok TS
AD  - Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of 
      Wales Hospital, Shatin, N.T., Hong Kong.
FAU - Underwood, Malcolm J
AU  - Underwood MJ
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong.
FAU - Chen, George G
AU  - Chen GG
AD  - Department of Surgery, The Chinese University of Hong Kong, Prince of Wales 
      Hospital, Shatin, N.T., Hong Kong. gchen@cuhk.edu.hk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150605
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Nitrosamines)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Estrogen Receptor alpha/*metabolism
MH  - Humans
MH  - Lung Neoplasms/etiology/*pathology/physiopathology/therapy
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Nitrosamines/pharmacology
OTO - NOTNLM
OT  - CYP1B1
OT  - ERK/AP1
OT  - ERalpha
OT  - Lung cancer
OT  - Smoking carcinogen NNK
EDAT- 2015/06/05 06:00
MHDA- 2016/08/27 06:00
CRDT- 2015/06/05 06:00
PHST- 2015/02/17 00:00 [received]
PHST- 2015/05/16 00:00 [accepted]
PHST- 2015/04/28 00:00 [revised]
PHST- 2015/06/05 06:00 [entrez]
PHST- 2015/06/05 06:00 [pubmed]
PHST- 2016/08/27 06:00 [medline]
AID - 10.1007/s00109-015-1300-4 [pii]
AID - 10.1007/s00109-015-1300-4 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2015 Nov;93(11):1221-33. doi: 10.1007/s00109-015-1300-4. Epub 
      2015 Jun 5.